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  • Review Article
  • Published:

Nitric oxide signalling in cardiovascular health and disease

Key Points

  • The three isoforms of nitric oxide synthase subserve distinct, but coordinated, functions through their subcellular confinement in cardiac and vascular cells

  • The redox environment dictates the fate of nitric oxide and pathophysiological effects

  • Multiple regulatory points of downstream effectors ensure signalling specificity and allow therapeutic modulation

  • New techniques for monitoring nitric oxide bioavailability will allow efficient tailoring of treatment

Abstract

Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. Tremendous knowledge has been accumulated on the mechanisms of the nitric oxide synthase (NOS)–NO pathway, but how this highly reactive, free radical gas signals to specific targets for precise regulation of cardiovascular function remains the focus of much intense research. In this Review, we summarize the updated paradigms on NOS regulation, NO interaction with reactive oxidant species in specific subcellular compartments, and downstream effects of NO in target cardiovascular tissues, while emphasizing the latest developments of molecular tools and biomarkers to modulate and monitor NO production and bioavailability.

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Figure 1: NOS–NO signalling in cardiovascular tissues.
Figure 2: Regulation of cardiac myocyte function by specific nitric oxide synthases.
Figure 3: NOS–NO pathway in vascular beds in health and disease.
Figure 4: NOS–NO pathway and therapeutic targets.

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References

  1. Kwon, N. S. et al. L-Citrulline production from L-arginine by macrophage nitric oxide synthase. The ureido oxygen derives from dioxygen. J. Biol. Chem. 265, 13442–13445 (1990).

    CAS  PubMed  Google Scholar 

  2. Busse, R. & Mulsch, A. Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin. FEBS Lett. 265, 133–136 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Stuehr, D. J., Cho, H. J., Kwon, N. S., Weise, M. F. & Nathan, C. F. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc. Natl Acad. Sci. USA 88, 7773–7777 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stuehr, D. J., Santolini, J., Wang, Z. Q., Wei, C. C. & Adak, S. Update on mechanism and catalytic regulation in the NO synthases. J. Biol. Chem. 279, 36167–36170 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Xia, Y., Tsai, A. L., Berka, V. & Zweier, J. L. Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. J. Biol. Chem. 273, 25804–25808 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Palmer, R. M., Ashton, D. S. & Moncada, S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333, 664–666 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. Balligand, J. L. et al. Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes. J. Biol. Chem. 270, 14582–14586 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Petroff, M. G. et al. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat. Cell Biol. 3, 867–873 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Wallerath, T. et al. Identification of the NO synthase isoforms expressed in human neutrophil granulocytes, megakaryocytes and platelets. Thromb. Haemost. 77, 163–167 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Kleinbongard, P. et al. Red blood cells express a functional endothelial nitric oxide synthase. Blood 107, 2943–2951 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Cortese-Krott, M. M. et al. Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease. Blood 120, 4229–4237 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Balligand, J. L., Feron, O. & Dessy, C. eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol. Rev. 89, 481–534 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Dimmeler, S. et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399, 601–605 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Fisslthaler, B., Loot, A. E., Mohamed, A., Busse, R. & Fleming, I. Inhibition of endothelial nitric oxide synthase activity by proline-rich tyrosine kinase 2 in response to fluid shear stress and insulin. Circ. Res. 102, 1520–1528 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Mattagajasingh, I. et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl Acad. Sci. USA 104, 14855–14860 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Feron, O., Michel, J. B., Sase, K. & Michel, T. Dynamic regulation of endothelial nitric oxide synthase: complementary roles of dual acylation and caveolin interactions. Biochemistry 37, 193–200 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Erwin, P. A., Lin, A. J., Golan, D. E. & Michel, T. Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in vascular endothelial cells. J. Biol. Chem. 280, 19888–19894 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Chen, C. A. et al. S-Glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468, 1115–1118 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yeh, D. C., Duncan, J. A., Yamashita, S. & Michel, T. Depalmitoylation of endothelial nitric-oxide synthase by acyl-protein thioesterase 1 is potentiated by Ca2+-calmodulin. J. Biol. Chem. 274, 33148–33154 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Feron, O. et al. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J. Biol. Chem. 271, 22810–22814 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Garcia-Cardena, G. et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 392, 821–824 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Fulton, D. et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597–601 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fleming, I., Fisslthaler, B., Dimmeler, S., Kemp, B. E. & Busse, R. Phosphorylation of Thr(495) regulates Ca2+/calmodulin-dependent endothelial nitric oxide synthase activity. Circ. Res. 88, E68–E75 (2001).

    CAS  PubMed  Google Scholar 

  24. Kupatt, C. et al. Heat shock protein 90 transfection reduces ischemia-reperfusion-induced myocardial dysfunction via reciprocal endothelial NO synthase serine 1177 phosphorylation and threonine 495 dephosphorylation. Arterioscler. Thromb. Vasc. Biol. 24, 1435–1441 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, M. et al. Pim1 kinase promotes angiogenesis through phosphorylation of endothelial nitric oxide synthase at Ser-633. Cardiovasc. Res. 109, 141–150 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Bibli, S. I. et al. Tyrosine phosphorylation of eNOS regulates myocardial survival after an ischaemic insult: role of PYK2. Cardiovasc. Res. 113, 926–937 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Xu, K. Y., Huso, D. L., Dawson, T. M., Bredt, D. S. & Becker, L. C. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc. Natl Acad. Sci. USA 96, 657–662 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Choate, J. K., Danson, E. J., Morris, J. F. & Paterson, D. J. Peripheral vagal control of heart rate is impaired in neuronal NOS knockout mice. Am. J. Physiol. Heart Circ. Physiol. 281, H2310–H2317 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Schwarz, P. M., Kleinert, H. & Forstermann, U. Potential functional significance of brain-type and muscle-type nitric oxide synthase I expressed in adventitia and media of rat aorta. Arterioscler. Thromb. Vasc. Biol. 19, 2584–2590 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Piech, A., Dessy, C., Havaux, X., Feron, O. & Balligand, J. L. Differential regulation of nitric oxide synthases and their allosteric regulators in heart and vessels of hypertensive rats. Cardiovasc. Res. 57, 456–467 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Brenman, J. E. et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell 84, 757–767 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Lai, Y. et al. Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J. Clin. Invest. 119, 624–635 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Williams, J. C. et al. The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex. J. Biol. Chem. 281, 23341–23348 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Reilly, S. N. et al. Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase. Sci. Transl Med. 8, 340ra74 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eliasson, M. J., Blackshaw, S., Schell, M. J. & Snyder, S. H. Neuronal nitric oxide synthase alternatively spliced forms: prominent functional localizations in the brain. Proc. Natl Acad. Sci. USA 94, 3396–3401 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fang, M. et al. Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON. Neuron 28, 183–193 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Kapoor, A. et al. An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval. Am. J. Hum. Genet. 94, 854–869 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chang, K. C. et al. CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart. Proc. Natl Acad. Sci. USA 105, 4477–4482 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Arking, D. E. et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat. Genet. 38, 644–651 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Tobin, M. D. et al. Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations. Int. J. Epidemiol. 37, 1132–1141 (2008).

    Article  PubMed  Google Scholar 

  41. Tomas, M. et al. Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome. J. Am. Coll. Cardiol. 55, 2745–2752 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Kolder, I. et al. Analysis for genetic modifiers of disease severity in patients with long-QT syndrome type 2. Circ. Cardiovasc. Genet. 8, 447–456 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Earle, N. J. et al. Genetic markers of repolarization and arrhythmic events after acute coronary syndromes. Am. Heart J. 169, 579–586.e3 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Verweij, N. et al. Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram. Hum. Mol. Genet. 25, 2093–2103 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nunez, L. et al. Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism. Cardiovasc. Res. 72, 80–89 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Gomez, R. et al. Nitric oxide inhibits Kv4.3 and human cardiac transient outward potassium current (Ito1). Cardiovasc. Res. 80, 375–384 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Lekontseva, O., Chakrabarti, S., Jiang, Y., Cheung, C. C. & Davidge, S. T. Role of neuronal nitric-oxide synthase in estrogen-induced relaxation in rat resistance arteries. J. Pharmacol. Exp. Ther. 339, 367–375 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Adak, S. et al. Neuronal nitric-oxide synthase mutant (Ser-1412 → Asp) demonstrates surprising connections between heme reduction, NO complex formation, and catalysis. J. Biol. Chem. 276, 1244–1252 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Trappanese, D. M. et al. Chronic beta1-adrenergic blockade enhances myocardial beta3-adrenergic coupling with nitric oxide-cGMP signaling in a canine model of chronic volume overload: new insight into mechanisms of cardiac benefit with selective beta1-blocker therapy. Bas. Res. Cardiol. 110, 456 (2015).

    Article  CAS  Google Scholar 

  50. Kar, R., Kellogg, D. L. III & Roman, L. J. Oxidative stress induces phosphorylation of neuronal NOS in cardiomyocytes through AMP-activated protein kinase (AMPK). Biochem. Biophys. Res. Commun. 459, 393–397 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jaffrey, S. R. & Snyder, S. H. PIN: an associated protein inhibitor of neuronal nitric oxide synthase. Science 274, 774–777 (1996).

    Article  CAS  PubMed  Google Scholar 

  52. Hemmens, B. et al. The protein inhibitor of neuronal nitric oxide synthase (PIN): characterization of its action on pure nitric oxide synthases. FEBS Lett. 430, 397–400 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Xia, Y., Berlowitz, C. O. & Zweier, J. L. PIN inhibits nitric oxide and superoxide production from purified neuronal nitric oxide synthase. Biochim. Biophys. Acta 1760, 1445–1449 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Barouch, L. A. et al. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 416, 337–339 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Zhang, Y. H. & Casadei, B. Sub-cellular targeting of constitutive NOS in health and disease. J. Mol. Cell. Cardiol. 52, 341–350 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Wilcox, J. N. et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler. Thromb. Vasc. Biol. 17, 2479–2488 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Balligand, J. L. et al. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J. Biol. Chem. 269, 27580–27588 (1994).

    CAS  PubMed  Google Scholar 

  58. de Vera, M. E. et al. Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter. Proc. Natl Acad. Sci. USA 93, 1054–1059 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pautz, A. et al. Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 23, 75–93 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. MacMicking, J., Xie, Q. W. & Nathan, C. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15, 323–350 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Haywood, G. A. et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation 93, 1087–1094 (1996).

    Article  CAS  PubMed  Google Scholar 

  62. Maron, B. A., Tang, S. S. & Loscalzo, J. S-Nitrosothiols and the S-nitrosoproteome of the cardiovascular system. Antioxid. Redox Signal. 18, 270–287 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Martinez-Ruiz, A. & Lamas, S. Detection and proteomic identification of S-nitrosylated proteins in endothelial cells. Arch. Biochem. Biophys. 423, 192–199 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Straub, A. C. et al. Endothelial cell expression of haemoglobin alpha regulates nitric oxide signalling. Nature 491, 473–477 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kleschyov, A. L. The NO-heme signaling hypothesis. Free Radic. Biol. Med. 112, 544–552 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Montfort, W. R., Wales, J. A. & Weichsel, A. Structure and activation of soluble guanylyl cyclase, the nitric oxide sensor. Antioxid. Redox Signal. 26, 107–121 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zaccolo, M. & Movsesian, M. A. cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ. Res. 100, 1569–1578 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Weber, S. et al. PDE2 at the crossway between cAMP and cGMP signalling in the heart. Cell Signal. 38, 76–84 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Munzel, T. et al. Physiology and pathophysiology of vascular signaling controlled by guanosine 3′,5′-cyclic monophosphate-dependent protein kinase [corrected]. Circulation 108, 2172–2183 (2003).

    Article  PubMed  Google Scholar 

  70. Massion, P. B. & Balligand, J. L. Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice. J. Physiol. 546, 63–75 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Surks, H. K. et al. Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha. Science 286, 1583–1587 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Klein, G., Drexler, H. & Schroder, F. Protein kinase G reverses all isoproterenol induced changes of cardiac single L-type calcium channel gating. Cardiovasc. Res. 48, 367–374 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Wollert, K. C. et al. Increased effects of C-type natriuretic peptide on contractility and calcium regulation in murine hearts overexpressing cyclic GMP-dependent protein kinase I. Br. J. Pharmacol. 140, 1227–1236 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee, D. I. et al. PDE5A suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation. Bas. Res. Cardiol. 105, 337–347 (2010).

    Article  CAS  Google Scholar 

  75. Hamdani, N., Bishu, K. G., von Frieling-Salewsky, M., Redfield, M. M. & Linke, W. A. Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction. Cardiovasc. Res. 97, 464–471 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Kruger, M. et al. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ. Res. 104, 87–94 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Burgoyne, J. R. et al. Cysteine redox sensor in PKGIa enables oxidant-induced activation. Science 317, 1393–1397 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Scotcher, J. et al. Disulfide-activated protein kinase G Ialpha regulates cardiac diastolic relaxation and fine-tunes the Frank-Starling response. Nat. Commun. 7, 13187 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Khavandi, K. et al. Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels. Sci. Signal. 9, ra100 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Murphy, E. et al. Signaling by S-nitrosylation in the heart. J. Mol. Cell. Cardiol. 73, 18–25 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lima, B., Forrester, M. T., Hess, D. T. & Stamler, J. S. S-Nitrosylation in cardiovascular signaling. Circ. Res. 106, 633–646 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chouchani, E. T. et al. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat. Med. 19, 753–759 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhang, R., Hess, D. T., Reynolds, J. D. & Stamler, J. S. Hemoglobin S-nitrosylation plays an essential role in cardioprotection. J. Clin. Invest. 126, 4654–4658 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Sun, J. et al. Ischaemic preconditioning preferentially increases protein S-nitrosylation in subsarcolemmal mitochondria. Cardiovasc. Res. 106, 227–236 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gonzalez, D. R., Beigi, F., Treuer, A. V. & Hare, J. M. Deficient ryanodine receptor S-nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes. Proc. Natl Acad. Sci. USA 104, 20612–20617 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Sun, J. et al. Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel alpha1 subunit and reduced ischemia/reperfusion injury. Circ. Res. 98, 403–411 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Irie, T. et al. S-Nitrosylation of calcium-handling proteins in cardiac adrenergic signaling and hypertrophy. Circ. Res. 117, 793–803 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Figueiredo-Freitas, C. et al. S-Nitrosylation of sarcomeric proteins depresses myofilament Ca2+ sensitivity in intact cardiomyocytes. Antioxid. Redox Signal. 23, 1017–1034 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jia, L., Bonaventura, C., Bonaventura, J. & Stamler, J. S. S-Nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature 380, 221–226 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Cai, Z. et al. Endothelial nitric oxide synthase-derived nitric oxide prevents dihydrofolate reductase degradation via promoting S-nitrosylation. Arterioscler. Thromb. Vasc. Biol. 35, 2366–2373 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sayed, N., Baskaran, P., Ma, X., van den Akker, F. & Beuve, A. Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation. Proc. Natl Acad. Sci. USA 104, 12312–12317 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu, L. et al. A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature 410, 490–494 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Hatzistergos, K. E. et al. S-Nitrosoglutathione reductase deficiency enhances the proliferative expansion of adult heart progenitors and myocytes post myocardial infarction. J. Am. Heart Assoc. 4, e001974 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu, L. et al. Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock. Cell 116, 617–628 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Beigi, F. et al. Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function. Proc. Natl Acad. Sci. USA 109, 4314–4319 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Yang, G. et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322, 587–590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Coletta, C. et al. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc. Natl Acad. Sci. USA 109, 9161–9166 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Altaany, Z., Ju, Y., Yang, G. & Wang, R. The coordination of S-sulfhydration, S-nitrosylation, and phosphorylation of endothelial nitric oxide synthase by hydrogen sulfide. Sci. Signal. 7, ra87 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Kanagy, N. L., Szabo, C. & Papapetropoulos, A. Vascular biology of hydrogen sulfide. Am. J. Physiol. Cell Physiol. 312, C537–C549 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Zhou, Z. et al. Regulation of soluble guanylyl cyclase redox state by hydrogen sulfide. Pharmacol. Res. 111, 556–562 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bucci, M. et al. Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arterioscler. Thromb. Vasc. Biol. 30, 1998–2004 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Stubbert, D. et al. Protein kinase G Ialpha oxidation paradoxically underlies blood pressure lowering by the reductant hydrogen sulfide. Hypertension 64, 1344–1351 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. King, A. L. et al. Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc. Natl Acad. Sci. USA 111, 3182–3187 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bibli, S. I. et al. Cardioprotection by H2S engages a cGMP-dependent protein kinase G/phospholamban pathway. Cardiovasc. Res. 106, 432–442 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jian, Z. et al. Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling. Sci. Signal. 7, ra27 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ashley, E. A., Sears, C. E., Bryant, S. M., Watkins, H. C. & Casadei, B. Cardiac nitric oxide synthase 1 regulates basal and beta-adrenergic contractility in murine ventricular myocytes. Circulation 105, 3011–3016 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Wang, H., Kohr, M. J., Wheeler, D. G. & Ziolo, M. T. Endothelial nitric oxide synthase decreases beta-adrenergic responsiveness via inhibition of the L-type Ca2+ current. Am. J. Physiol. Heart Circ. Physiol. 294, H1473–H1480 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Sears, C. E. et al. Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. Circ. Res. 92, e52–e59 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Brown, G. C. & Borutaite, V. Nitric oxide and mitochondrial respiration in the heart. Cardiovasc. Res. 75, 283–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Balligand, J. L., Kelly, R. A., Marsden, P. A., Smith, T. W. & Michel, T. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc. Natl Acad. Sci. USA 90, 347–351 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Massion, P. B., Feron, O., Dessy, C. & Balligand, J. L. Nitric oxide and cardiac function: ten years after, and continuing. Circ. Res. 93, 388–398 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Martin, S. R., Emanuel, K., Sears, C. E., Zhang, Y. H. & Casadei, B. Are myocardial eNOS and nNOS involved in the beta-adrenergic and muscarinic regulation of inotropy? A systematic investigation. Cardiovasc. Res. 70, 97–106 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Gauthier, C. et al. The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J. Clin. Invest. 102, 1377–1384 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tavernier, G. et al. Beta3-adrenergic stimulation produces a decrease of cardiac contractility ex vivo in mice overexpressing the human beta3-adrenergic receptor. Cardiovasc. Res. 59, 288–296 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Varghese, P. et al. Beta3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility. J. Clin. Invest. 106, 697–703 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Idigo, W. O. et al. Regulation of endothelial nitric-oxide synthase (NOS) S-glutathionylation by neuronal NOS: evidence of a functional interaction between myocardial constitutive NOS isoforms. J. Biol. Chem. 287, 43665–43673 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gallo, M. P. et al. Modulation of guinea-pig cardiac L-type calcium current by nitric oxide synthase inhibitors. J. Physiol. 506, 639–651 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Poteser, M., Romanin, C., Schreibmayer, W., Mayer, B. & Groschner, K. S-Nitrosation controls gating and conductance of the alpha 1 subunit of class C L-type Ca(2+) channels. J. Biol. Chem. 276, 14797–14803 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Layland, J., Li, J. M. & Shah, A. M. Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes. J. Physiol. 540, 457–467 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kohlhaas, M. et al. Endogenous nitric oxide formation in cardiac myocytes does not control respiration during beta-adrenergic stimulation. J. Physiol. 595, 3781–3798 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cutler, M. J. et al. Aberrant S-nitrosylation mediates calcium-triggered ventricular arrhythmia in the intact heart. Proc. Natl Acad. Sci. USA 109, 18186–18191 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Fauconnier, J. et al. Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy. Proc. Natl Acad. Sci. USA 107, 1559–1564 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Wang, H. et al. Regulation of myocyte contraction via neuronal nitric oxide synthase: role of ryanodine receptor S-nitrosylation. J. Physiol. 588, 2905–2917 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhang, Y. H. et al. Reduced phospholamban phosphorylation is associated with impaired relaxation in left ventricular myocytes from neuronal NO synthase-deficient mice. Circ. Res. 102, 242–249 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Khan, S. A. et al. Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. Proc. Natl Acad. Sci. USA 101, 15944–15948 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Carnicer, R. et al. The subcellular localisation of neuronal nitric oxide synthase determines the downstream effects of NO on myocardial function. Cardiovasc. Res. 113, 321–331 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Damy, T. et al. Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet 363, 1365–1367 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Paulus, W. J., Vantrimpont, P. J. & Shah, A. M. Paracrine coronary endothelial control of left ventricular function in humans. Circulation 92, 2119–2126 (1995).

    Article  CAS  PubMed  Google Scholar 

  129. Godecke, A. et al. Inotropic response to beta-adrenergic receptor stimulation and anti-adrenergic effect of ACh in endothelial NO synthase-deficient mouse hearts. J. Physiol. 532, 195–204 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Liu, X. et al. Cytoglobin regulates blood pressure and vascular tone through nitric oxide metabolism in the vascular wall. Nat. Commun. 8, 14807 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Santizo, R., Baughman, V. L. & Pelligrino, D. A. Relative contributions from neuronal and endothelial nitric oxide synthases to regional cerebral blood flow changes during forebrain ischemia in rats. Neuroreport 11, 1549–1553 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Gotoh, J. et al. Regional differences in mechanisms of cerebral circulatory response to neuronal activation. Am. J. Physiol. Heart Circ. Physiol. 280, H821–H829 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Kurihara, N. et al. Role of nNOS in blood pressure regulation in eNOS null mutant mice. Hypertension 32, 856–861 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. Toda, N. & Okamura, T. Modulation of renal blood flow and vascular tone by neuronal nitric oxide synthase-derived nitric oxide. J. Vasc. Res. 48, 1–10 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Huang, A. et al. Neuronal NOS-dependent dilation to flow in coronary arteries of male eNOS-KO mice. Am. J. Physiol. Heart Circ. Physiol. 282, H429–H436 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Seddon, M. D., Chowienczyk, P. J., Brett, S. E., Casadei, B. & Shah, A. M. Neuronal nitric oxide synthase regulates basal microvascular tone in humans in vivo. Circulation 117, 1991–1996 (2008).

    Article  CAS  PubMed  Google Scholar 

  137. Seddon, M. et al. Effects of neuronal nitric oxide synthase on human coronary artery diameter and blood flow in vivo. Circulation 119, 2656–2662 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Shabeeh, H. et al. Blood pressure in healthy humans is regulated by neuronal NO synthase. Hypertension 69, 970–976 (2017).

    Article  CAS  PubMed  Google Scholar 

  139. Thomas, G. D. et al. Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc. Natl Acad. Sci. USA 95, 15090–15095 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Thomas, G. D., Shaul, P. W., Yuhanna, I. S., Froehner, S. C. & Adams, M. E. Vasomodulation by skeletal muscle-derived nitric oxide requires alpha-syntrophin-mediated sarcolemmal localization of neuronal Nitric oxide synthase. Circ. Res. 92, 554–560 (2003).

    Article  CAS  PubMed  Google Scholar 

  141. Schwarz, P., Diem, R., Dun, N. J. & Forstermann, U. Endogenous and exogenous nitric oxide inhibits norepinephrine release from rat heart sympathetic nerves. Circ. Res. 77, 841–848 (1995).

    Article  CAS  PubMed  Google Scholar 

  142. Herring, N., Golding, S. & Paterson, D. J. Pre-synaptic NO-cGMP pathway modulates vagal control of heart rate in isolated adult guinea pig atria. J. Mol. Cell. Cardiol. 32, 1795–1804 (2000).

    Article  CAS  PubMed  Google Scholar 

  143. Massion, P. B. et al. Cardiomyocyte-restricted overexpression of endothelial nitric oxide synthase (NOS3) attenuates beta-adrenergic stimulation and reinforces vagal inhibition of cardiac contraction. Circulation 110, 2666–2672 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Packer, M. Neurohormonal interactions and adaptations in congestive heart failure. Circulation 77, 721–730 (1988).

    Article  CAS  PubMed  Google Scholar 

  145. Florea, V. G. & Cohn, J. N. The autonomic nervous system and heart failure. Circ. Res. 114, 1815–1826 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Soltis, E. E. & Cassis, L. A. Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin. Exp. Hypertens. A 13, 277–296 (1991).

    CAS  PubMed  Google Scholar 

  147. Victorio, J. A., Fontes, M. T., Rossoni, L. V. & Davel, A. P. Different anti-contractile function and nitric oxide production of thoracic and abdominal perivascular adipose tissues. Front. Physiol. 7, 295 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Greenstein, A. S. et al. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119, 1661–1670 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Gil-Ortega, M. et al. Adaptative nitric oxide overproduction in perivascular adipose tissue during early diet-induced obesity. Endocrinology 151, 3299–3306 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Fang, L. et al. Hydrogen sulfide derived from periadventitial adipose tissue is a vasodilator. J. Hypertens. 27, 2174–2185 (2009).

    Article  CAS  PubMed  Google Scholar 

  151. Schleifenbaum, J. et al. Systemic peripheral artery relaxation by KCNQ channel openers and hydrogen sulfide. J. Hypertens. 28, 1875–1882 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Gao, Y. J., Lu, C., Su, L. Y., Sharma, A. M. & Lee, R. M. Modulation of vascular function by perivascular adipose tissue: the role of endothelium and hydrogen peroxide. Br. J. Pharmacol. 151, 323–331 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lee, Y. C. et al. Role of perivascular adipose tissue-derived methyl palmitate in vascular tone regulation and pathogenesis of hypertension. Circulation 124, 1160–1171 (2011).

    Article  PubMed  Google Scholar 

  154. Lee, R. M., Lu, C., Su, L. Y. & Gao, Y. J. Endothelium-dependent relaxation factor released by perivascular adipose tissue. J. Hypertens. 27, 782–790 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Sampaio, W. O. et al. Angiotensin-(1–7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension 49, 185–192 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Weston, A. H. et al. Stimulated release of a hyperpolarizing factor (ADHF) from mesenteric artery perivascular adipose tissue: involvement of myocyte BKCa channels and adiponectin. Br. J. Pharmacol. 169, 1500–1509 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Xi, W., Satoh, H., Kase, H., Suzuki, K. & Hattori, Y. Stimulated HSP90 binding to eNOS and activation of the PI3-Akt pathway contribute to globular adiponectin-induced NO production: vasorelaxation in response to globular adiponectin. Biochem. Biophys. Res. Commun. 332, 200–205 (2005).

    Article  CAS  PubMed  Google Scholar 

  158. Margaritis, M. et al. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation 127, 2209–2221 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Lundberg, J. O. et al. Nitrate and nitrite in biology, nutrition and therapeutics. Nat. Chem. Biol. 5, 865–869 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Cosby, K. et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat. Med. 9, 1498–1505 (2003).

    Article  CAS  PubMed  Google Scholar 

  161. Liu, C. et al. Mechanisms of human erythrocytic bioactivation of nitrite. J. Biol. Chem. 290, 1281–1294 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Pawloski, J. R., Hess, D. T. & Stamler, J. S. Export by red blood cells of nitric oxide bioactivity. Nature 409, 622–626 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Zhang, R. et al. Hemoglobin betaCys93 is essential for cardiovascular function and integrated response to hypoxia. Proc. Natl Acad. Sci. USA 112, 6425–6430 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Isbell, T. S. et al. SNO-hemoglobin is not essential for red blood cell-dependent hypoxic vasodilation. Nat. Med. 14, 773–777 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Lobysheva, I. I., Biller, P., Gallez, B., Beauloye, C. & Balligand, J. L. Nitrosylated hemoglobin levels in human venous erythrocytes correlate with vascular endothelial function measured by digital reactive hyperemia. PLoS ONE 8, e76457 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Lobysheva, I. I. et al. Heme-nitrosylated hemoglobin and oxidative stress in women consuming combined contraceptives. Clinical application of the EPR spectroscopy. Free Radic. Biol. Med. 108, 524–532 (2017).

    Article  CAS  PubMed  Google Scholar 

  167. Erkens, R. et al. Modulation of local and systemic heterocellular communication by mechanical forces: a role of endothelial nitric oxide synthase. Antioxid. Redox Signal. 26, 917–935 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Kuhn, V. et al. Red blood cell function and dysfunction: redox regulation, nitric oxide metabolism. Anemia. Antioxid. Redox Signal. 26, 718–742 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Zweier, J. L., Chen, C. A. & Druhan, L. J. S-Glutathionylation reshapes our understanding of endothelial nitric oxide synthase uncoupling and nitric oxide/reactive oxygen species-mediated signaling. Antioxid. Redox Signal. 14, 1769–1775 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Xia, Y., Dawson, V. L., Dawson, T. M., Snyder, S. H. & Zweier, J. L. Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc. Natl Acad. Sci. USA 93, 6770–6774 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Xia, Y. & Zweier, J. L. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc. Natl Acad. Sci. USA 94, 6954–6958 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ramachandran, J. & Peluffo, R. D. Threshold levels of extracellular l-arginine that trigger NOS-mediated ROS/RNS production in cardiac ventricular myocytes. Am. J. Physiol. Cell Physiol. 312, C144–C154 (2017).

    Article  PubMed  Google Scholar 

  173. Antoniades, C. et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur. Heart J. 30, 1142–1150 (2009).

    Article  CAS  PubMed  Google Scholar 

  174. Cardounel, A. J., Xia, Y. & Zweier, J. L. Endogenous methylarginines modulate superoxide as well as nitric oxide generation from neuronal nitric-oxide synthase: differences in the effects of monomethyl- and dimethylarginines in the presence and absence of tetrahydrobiopterin. J. Biol. Chem. 280, 7540–7549 (2005).

    Article  CAS  PubMed  Google Scholar 

  175. Druhan, L. J. et al. Regulation of eNOS-derived superoxide by endogenous methylarginines. Biochemistry 47, 7256–7263 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Ryoo, S. et al. Oxidized low-density lipoprotein-dependent endothelial arginase II activation contributes to impaired nitric oxide signaling. Circ. Res. 99, 951–960 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Shemyakin, A. et al. Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus. Circulation 126, 2943–2950 (2012).

    Article  CAS  PubMed  Google Scholar 

  178. Zhou, S. et al. Asymmetric dimethylarginine and all-cause mortality: a systematic review and meta-analysis. Sci. Rep. 7, 44692 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Bendall, J. K. et al. Stoichiometric relationships between endothelial tetrahydrobiopterin, endothelial NO synthase (eNOS) activity, and eNOS coupling in vivo: insights from transgenic mice with endothelial-targeted GTP cyclohydrolase 1 and eNOS overexpression. Circ. Res. 97, 864–871 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Dumitrescu, C. et al. Myocardial ischemia results in tetrahydrobiopterin (BH4) oxidation with impaired endothelial function ameliorated by BH4. Proc. Natl Acad. Sci. USA 104, 15081–15086 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Crabtree, M. J., Tatham, A. L., Hale, A. B., Alp, N. J. & Channon, K. M. Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways. J. Biol. Chem. 284, 28128–28136 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Moens, A. L. et al. Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure. J. Mol. Cell. Cardiol. 51, 564–569 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Reilly, S. N. et al. Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins. Circulation 124, 1107–1117 (2011).

    Article  CAS  PubMed  Google Scholar 

  184. Schmidt, T. S. & Alp, N. J. Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease. Clin. Sci. 113, 47–63 (2007).

    Article  CAS  Google Scholar 

  185. Moens, A. L. et al. Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: efficacy of recoupling nitric oxide synthase as a therapeutic strategy. Circulation 117, 2626–2636 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Nishijima, Y. et al. Tetrahydrobiopterin depletion and NOS2 uncoupling contribute to heart failure-induced alterations in atrial electrophysiology. Cardiovasc. Res. 91, 71–79 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Tiefenbacher, C. P. et al. Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis. Circulation 102, 2172–2179 (2000).

    Article  CAS  PubMed  Google Scholar 

  188. Alp, N. J. et al. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J. Clin. Invest. 112, 725–735 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Chen, W. et al. Peroxynitrite induces destruction of the tetrahydrobiopterin and heme in endothelial nitric oxide synthase: transition from reversible to irreversible enzyme inhibition. Biochemistry 49, 3129–3137 (2010).

    Article  CAS  PubMed  Google Scholar 

  190. Reyes, L. A. et al. Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart. Proc. Natl Acad. Sci. USA 112, 11648–11653 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Kojima, S. et al. Antioxidative activity of 5,6,7,8-tetrahydrobiopterin and its inhibitory effect on paraquat-induced cell toxicity in cultured rat hepatocytes. Free Radic. Res. 23, 419–430 (1995).

    Article  CAS  PubMed  Google Scholar 

  192. Bailey, J. et al. A novel role for endothelial tetrahydrobiopterin in mitochondrial redox balance. Free Radic. Biol. Med. 104, 214–225 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Antoniades, C. et al. Induction of vascular GTP-cyclohydrolase I and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis. Circulation 124, 1860–1870 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Hashimoto, T. et al. Tetrahydrobiopterin protects against hypertrophic heart disease independent of myocardial nitric oxide synthase coupling. J. Am. Heart Assoc. 5, e003208 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Chen, Z. et al. Shear stress, SIRT1, and vascular homeostasis. Proc. Natl Acad. Sci. USA 107, 10268–10273 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Maizel, J. et al. Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction. Am. J. Physiol. Heart Circ. Physiol. 307, H1691–H1704 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Nagar, H. et al. CR6-interacting factor 1 deficiency impairs vascular function by inhibiting the Sirt1-endothelial nitric oxide synthase pathway. Antioxid. Redox Signal. 27, 234–249 (2017).

    Article  CAS  PubMed  Google Scholar 

  198. Charles, S., Raj, V., Arokiaraj, J. & Mala, K. Caveolin1/protein arginine methyltransferase1/sirtuin1 axis as a potential target against endothelial dysfunction. Pharmacol. Res. 119, 1–11 (2017).

    Article  CAS  PubMed  Google Scholar 

  199. Sharina, I. G. & Martin, E. The role of reactive oxygen and nitrogen species in the expression and splicing of nitric oxide receptor. Antioxid. Redox Signal. 26, 122–136 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Stasch, J. P. et al. Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J. Clin. Invest. 116, 2552–2561 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ghosh, A. et al. Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma. Proc. Natl Acad. Sci. USA 113, E2355–2362 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Rahaman, M. M. et al. Cytochrome b5 reductase 3 modulates soluble guanylate cyclase redox state and cGMP signaling. Circ. Res. 121, 137–148 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Thoonen, R. et al. Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice. Nat. Commun. 6, 8482 (2015).

    Article  CAS  PubMed  Google Scholar 

  204. Fernhoff, N. B., Derbyshire, E. R., Underbakke, E. S. & Marletta, M. A. Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide. J. Biol. Chem. 287, 43053–43062 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Sayed, N. et al. Nitroglycerin-induced S-nitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance. Circ. Res. 103, 606–614 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Huang, C. et al. Guanylyl cyclase sensitivity to nitric oxide is protected by a thiol oxidation-driven interaction with thioredoxin-1. J. Biol. Chem. 292, 14362–14370 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Yasmin, W., Strynadka, K. D. & Schulz, R. Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. Cardiovasc. Res. 33, 422–432 (1997).

    Article  CAS  PubMed  Google Scholar 

  208. Saraiva, R. M. et al. Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction: role of nitroso-redox equilibrium. Circulation 112, 3415–3422 (2005).

    Article  CAS  PubMed  Google Scholar 

  209. Dawson, D. et al. nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. Circulation 112, 3729–3737 (2005).

    Article  CAS  PubMed  Google Scholar 

  210. Burger, D. E. et al. Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice. Circulation 120, 1345–1354 (2009).

    Article  CAS  PubMed  Google Scholar 

  211. Brunner, F. et al. Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Cardiovasc. Res. 57, 55–62 (2003).

    Article  CAS  PubMed  Google Scholar 

  212. Elrod, J. W. et al. Cardiomyocyte-specific overexpression of NO synthase-3 protects against myocardial ischemia-reperfusion injury. Arterioscler. Thromb. Vasc. Biol. 26, 1517–1523 (2006).

    Article  CAS  PubMed  Google Scholar 

  213. Szelid, Z. et al. Cardioselective nitric oxide synthase 3 gene transfer protects against myocardial reperfusion injury. Bas. Res. Cardiol. 105, 169–179 (2010).

    Article  CAS  Google Scholar 

  214. Janssens, S. et al. Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ. Res. 94, 1256–1262 (2004).

    Article  CAS  PubMed  Google Scholar 

  215. Burkard, N. et al. Conditional overexpression of neuronal nitric oxide synthase is cardioprotective in ischemia/reperfusion. Circulation 122, 1588–1603 (2010).

    Article  CAS  PubMed  Google Scholar 

  216. Korge, P., Ping, P. & Weiss, J. N. Reactive oxygen species production in energized cardiac mitochondria during hypoxia/reoxygenation: modulation by nitric oxide. Circ. Res. 103, 873–880 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Heusch, G., Boengler, K. & Schulz, R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118, 1915–1919 (2008).

    Article  PubMed  Google Scholar 

  218. Wang, P. & Zweier, J. L. Measurement of nitric oxide and peroxynitrite generation in the postischemic heart. Evidence for peroxynitrite-mediated reperfusion injury. J. Biol. Chem. 271, 29223–29230 (1996).

    Article  CAS  PubMed  Google Scholar 

  219. Flogel, U., Decking, U. K., Godecke, A. & Schrader, J. Contribution of NO to ischemia-reperfusion injury in the saline-perfused heart: a study in endothelial NO synthase knockout mice. J. Mol. Cell. Cardiol. 31, 827–836 (1999).

    Article  CAS  PubMed  Google Scholar 

  220. Csonka, C. et al. Classic preconditioning decreases the harmful accumulation of nitric oxide during ischemia and reperfusion in rat hearts. Circulation 100, 2260–2266 (1999).

    Article  CAS  PubMed  Google Scholar 

  221. de Waard, M. C. et al. Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 296, H1513–H1523 (2009).

    Article  CAS  PubMed  Google Scholar 

  222. Wajima, T., Shimizu, S., Hiroi, T., Ishii, M. & Kiuchi, Y. Reduction of myocardial infarct size by tetrahydrobiopterin: possible involvement of mitochondrial KATP channels activation through nitric oxide production. J. Cardiovasc. Pharmacol. 47, 243–249 (2006).

    Article  CAS  PubMed  Google Scholar 

  223. Xie, L., Talukder, M. A., Sun, J., Varadharaj, S. & Zweier, J. L. Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection. J. Mol. Cell. Cardiol. 86, 14–22 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Zhang, P. et al. Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ. Res. 100, 1089–1098 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Sam, F. et al. Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction. Circ. Res. 89, 351–356 (2001).

    Article  CAS  PubMed  Google Scholar 

  226. Feng, Q., Lu, X., Jones, D. L., Shen, J. & Arnold, J. M. Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 104, 700–704 (2001).

    Article  CAS  PubMed  Google Scholar 

  227. West, M. B. et al. Cardiac myocyte-specific expression of inducible nitric oxide synthase protects against ischemia/reperfusion injury by preventing mitochondrial permeability transition. Circulation 118, 1970–1978 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Guo, Y. et al. The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc. Natl Acad. Sci. USA 96, 11507–11512 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Bolli, R. Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research. J. Mol. Cell. Cardiol. 33, 1897–1918 (2001).

    Article  CAS  PubMed  Google Scholar 

  230. Yang, C., Talukder, M. A., Varadharaj, S., Velayutham, M. & Zweier, J. L. Early ischaemic preconditioning requires Akt- and PKA-mediated activation of eNOS via serine1176 phosphorylation. Cardiovasc. Res. 97, 33–43 (2013).

    Article  CAS  PubMed  Google Scholar 

  231. Wang, Y., Kudo, M., Xu, M., Ayub, A. & Ashraf, M. Mitochondrial K(ATP) channel as an end effector of cardioprotection during late preconditioning: triggering role of nitric oxide. J. Mol. Cell. Cardiol. 33, 2037–2046 (2001).

    Article  CAS  PubMed  Google Scholar 

  232. Sun, J., Morgan, M., Shen, R. F., Steenbergen, C. & Murphy, E. Preconditioning results in S-nitrosylation of proteins involved in regulation of mitochondrial energetics and calcium transport. Circ. Res. 101, 1155–1163 (2007).

    Article  CAS  PubMed  Google Scholar 

  233. Chouchani, E. T. et al. Identification and quantification of protein S-nitrosation by nitrite in the mouse heart during ischemia. J. Biol. Chem. 292, 14486–14495 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Takimoto, E. et al. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J. Clin. Invest. 115, 1221–1231 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. van Deel, E. D. et al. Normal and high eNOS levels are detrimental in both mild and severe cardiac pressure-overload. J. Mol. Cell. Cardiol. 88, 145–154 (2015).

    Article  CAS  PubMed  Google Scholar 

  236. Loyer, X. et al. Cardiomyocyte overexpression of neuronal nitric oxide synthase delays transition toward heart failure in response to pressure overload by preserving calcium cycling. Circulation 117, 3187–3198 (2008).

    Article  CAS  PubMed  Google Scholar 

  237. Hermida, N. et al. Cardiac myocyte b3-adrenergic receptors prevent myocardial fibrosis by modulating oxidant stress-dependent paracrine signaling. Eur. Heart J. http://dx.doi.org/10.1093/eurheartj/ehx366 (2017).

  238. Niu, X. et al. Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase. J. Am. Coll. Cardiol. 59, 1979–1987 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Belge, C. et al. Enhanced expression of beta3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation 129, 451–462 (2014).

    Article  CAS  PubMed  Google Scholar 

  240. Davignon, J. & Ganz, P. Role of endothelial dysfunction in atherosclerosis. Circulation 109, III-27–III-32 (2004).

    Google Scholar 

  241. Forstermann, U., Xia, N. & Li, H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ. Res. 120, 713–735 (2017).

    Article  CAS  PubMed  Google Scholar 

  242. Panza, J. A., Quyyumi, A. A., Brush, J. E. Jr & Epstein, S. E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N. Engl. J. Med. 323, 22–27 (1990).

    Article  CAS  PubMed  Google Scholar 

  243. Panza, J. A., Casino, P. R., Kilcoyne, C. M. & Quyyumi, A. A. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 87, 1468–1474 (1993).

    Article  CAS  PubMed  Google Scholar 

  244. Huang, P. L. et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377, 239–242 (1995).

    Article  CAS  PubMed  Google Scholar 

  245. Paolocci, N. et al. Oxygen radical-mediated reduction in basal and agonist-evoked NO release in isolated rat heart. J. Mol. Cell. Cardiol. 33, 671–679 (2001).

    Article  CAS  PubMed  Google Scholar 

  246. Li, H. et al. Reversal of endothelial nitric oxide synthase uncoupling and up-regulation of endothelial nitric oxide synthase expression lowers blood pressure in hypertensive rats. J. Am. Coll. Cardiol. 47, 2536–2544 (2006).

    Article  CAS  PubMed  Google Scholar 

  247. Alp, N. J., McAteer, M. A., Khoo, J., Choudhury, R. P. & Channon, K. M. Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice. Arterioscler. Thromb. Vasc. Biol. 24, 445–450 (2004).

    Article  CAS  PubMed  Google Scholar 

  248. Antoniades, C. et al. Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation. Circulation 116, 2851–2859 (2007).

    Article  CAS  PubMed  Google Scholar 

  249. Lobysheva, I. et al. Moderate caveolin-1 downregulation prevents NADPH oxidase-dependent endothelial nitric oxide synthase uncoupling by angiotensin II in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 31, 2098–2105 (2011).

    Article  CAS  PubMed  Google Scholar 

  250. Zhang, Q. J. et al. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovasc. Res. 80, 191–199 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Kadlec, A. O. et al. PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) overexpression in coronary artery disease recruits NO and hydrogen peroxide during flow-mediated dilation and protects against increased intraluminal pressure. Hypertension 70, 166–173 (2017).

    Article  CAS  PubMed  Google Scholar 

  252. Kuhlencordt, P. J. et al. Atheroprotective effects of neuronal nitric oxide synthase in apolipoprotein e knockout mice. Arterioscler. Thromb. Vasc. Biol. 26, 1539–1544 (2006).

    Article  CAS  PubMed  Google Scholar 

  253. Campos-Mota, G. P., Navia-Pelaez, J. M., Araujo-Souza, J. C., Stergiopulos, N. & Capettini, L. S. A. Role of ERK1/2 activation and nNOS uncoupling on endothelial dysfunction induced by lysophosphatidylcholine. Atherosclerosis 258, 108–118 (2017).

    Article  CAS  PubMed  Google Scholar 

  254. Kuhlencordt, P. J., Chen, J., Han, F., Astern, J. & Huang, P. L. Genetic deficiency of inducible nitric oxide synthase reduces atherosclerosis and lowers plasma lipid peroxides in apolipoprotein E-knockout mice. Circulation 103, 3099–3104 (2001).

    Article  CAS  PubMed  Google Scholar 

  255. Reventun, P. et al. iNOS-derived nitric oxide induces integrin-linked kinase endocytic lysosome-mediated degradation in the vascular endothelium. Arterioscler. Thromb. Vasc. Biol. 37, 1272–1281 (2017).

    Article  CAS  PubMed  Google Scholar 

  256. Herranz, B. et al. Integrin-linked kinase regulates vasomotor function by preventing endothelial nitric oxide synthase uncoupling: role in atherosclerosis. Circ. Res. 110, 439–449 (2012).

    Article  CAS  PubMed  Google Scholar 

  257. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  258. Vegiopoulos, A. et al. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328, 1158–1161 (2010).

    Article  CAS  PubMed  Google Scholar 

  259. Takx, R. A. et al. Supraclavicular brown adipose tissue 18F-FDG uptake and cardiovascular disease. J. Nuclear Med. 57, 1221–1225 (2016).

    Article  CAS  Google Scholar 

  260. Franssens, B. T., Hoogduin, H., Leiner, T., van der Graaf, Y. & Visseren, F. L. J. Relation between brown adipose tissue and measures of obesity and metabolic dysfunction in patients with cardiovascular disease. J. Magn. Reson. Imag. 46, 497–504 (2017).

    Article  Google Scholar 

  261. Chondronikola, M. et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63, 4089–4099 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Lee, P. et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63, 3686–3698 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Valerio, A. et al. TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J. Clin. Invest. 116, 2791–2798 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Wisloff, U. et al. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307, 418–420 (2005).

    Article  CAS  PubMed  Google Scholar 

  265. Nisoli, E. et al. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 299, 896–899 (2003).

    Article  CAS  PubMed  Google Scholar 

  266. Haas, B. et al. Protein kinase G controls brown fat cell differentiation and mitochondrial biogenesis. Sci. Signal. 2, ra78 (2009).

    Article  CAS  PubMed  Google Scholar 

  267. Kikuchi-Utsumi, K. et al. Enhanced gene expression of endothelial nitric oxide synthase in brown adipose tissue during cold exposure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R623–R626 (2002).

    Article  CAS  PubMed  Google Scholar 

  268. Oguri, Y. et al. Tetrahydrobiopterin activates brown adipose tissue and regulates systemic energy metabolism. JCI Insight http://dx.doi.org/10.1172/jci.insight.91981 (2017).

  269. Nisoli, E. et al. Effects of nitric oxide on proliferation and differentiation of rat brown adipocytes in primary cultures. Br. J. Pharmacol. 125, 888–894 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Roberts, L. D. et al. Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway. Diabetes 64, 471–484 (2015).

    Article  CAS  PubMed  Google Scholar 

  271. Miller, M. W. et al. Nitric oxide regulates vascular adaptive mitochondrial dynamics. Am. J. Physiol. Heart Circ. Physiol. 304, H1624–1633 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Nisoli, E. et al. Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc. Natl Acad. Sci. USA 101, 16507–16512 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  PubMed  Google Scholar 

  274. Lehman, J. J. et al. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J. Clin. Invest. 106, 847–856 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Nisoli, E. et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310, 314–317 (2005).

    Article  CAS  PubMed  Google Scholar 

  276. Vettor, R. et al. Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 306, E519–E528 (2014).

    Article  CAS  PubMed  Google Scholar 

  277. D'Antona, G. et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell. Metab. 12, 362–372 (2010).

    Article  CAS  PubMed  Google Scholar 

  278. Xia, N. et al. Uncoupling of endothelial nitric oxide synthase in perivascular adipose tissue of diet-induced obese mice. Arterioscler. Thromb. Vasc. Biol. 36, 78–85 (2016).

    Article  CAS  PubMed  Google Scholar 

  279. Xia, N. et al. Restoration of perivascular adipose tissue function in diet-induced obese mice without changing bodyweight. Br. J. Pharmacol. 174, 3443–3453 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Aghamohammadzadeh, R. et al. Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. J. Am. Coll. Cardiol. 62, 128–135 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  281. Virdis, A. et al. Tumour necrosis factor-alpha participates on the endothelin-1/nitric oxide imbalance in small arteries from obese patients: role of perivascular adipose tissue. Eur. Heart J. 36, 784–794 (2015).

    Article  CAS  PubMed  Google Scholar 

  282. Zweier, J. L., Wang, P., Samouilov, A. & Kuppusamy, P. Enzyme-independent formation of nitric oxide in biological tissues. Nat. Med. 1, 804–809 (1995).

    Article  CAS  PubMed  Google Scholar 

  283. Duncan, C. et al. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat. Med. 1, 546–551 (1995).

    Article  CAS  PubMed  Google Scholar 

  284. Benjamin, N. et al. Stomach NO synthesis. Nature 368, 502 (1994).

    Article  CAS  PubMed  Google Scholar 

  285. Lundberg, J. O., Weitzberg, E., Lundberg, J. M. & Alving, K. Intragastric nitric oxide production in humans: measurements in expelled air. Gut 35, 1543–1546 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Gladwin, M. T. et al. Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans. Proc. Natl Acad. Sci. USA 97, 11482–11487 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Huang, Z. et al. Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J. Clin. Invest. 115, 2099–2107 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Shiva, S. et al. Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ. Res. 100, 654–661 (2007).

    Article  CAS  PubMed  Google Scholar 

  289. Ormerod, J. O. et al. The role of vascular myoglobin in nitrite-mediated blood vessel relaxation. Cardiovasc. Res. 89, 560–565 (2011).

    Article  CAS  PubMed  Google Scholar 

  290. Rassaf, T. et al. Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function. Circ. Res. 100, 1749–1754 (2007).

    Article  CAS  PubMed  Google Scholar 

  291. Li, H., Samouilov, A., Liu, X. & Zweier, J. L. Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrite reduction. Evaluation of its role in nitric oxide generation in anoxic tissues. J. Biol. Chem. 276, 24482–24489 (2001).

    Article  CAS  PubMed  Google Scholar 

  292. Webb, A. J. et al. Mechanisms underlying erythrocyte and endothelial nitrite reduction to nitric oxide in hypoxia: role for xanthine oxidoreductase and endothelial nitric oxide synthase. Circ. Res. 103, 957–964 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Li, H., Kundu, T. K. & Zweier, J. L. Characterization of the magnitude and mechanism of aldehyde oxidase-mediated nitric oxide production from nitrite. J. Biol. Chem. 284, 33850–33858 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Castello, P. R., David, P. S., McClure, T., Crook, Z. & Poyton, R. O. Mitochondrial cytochrome oxidase produces nitric oxide under hypoxic conditions: implications for oxygen sensing and hypoxic signaling in eukaryotes. Cell. Metab. 3, 277–287 (2006).

    Article  CAS  PubMed  Google Scholar 

  295. Vanin, A. F., Bevers, L. M., Slama-Schwok, A. & van Faassen, E. E. Nitric oxide synthase reduces nitrite to NO under anoxia. Cell. Mol. Life Sci. 64, 96–103 (2007).

    Article  CAS  PubMed  Google Scholar 

  296. Gautier, C., van Faassen, E., Mikula, I., Martasek, P. & Slama-Schwok, A. Endothelial nitric oxide synthase reduces nitrite anions to NO under anoxia. Biochem. Biophys. Res. Commun. 341, 816–821 (2006).

    Article  CAS  PubMed  Google Scholar 

  297. Modin, A. et al. Nitrite-derived nitric oxide: a possible mediator of 'acidic-metabolic' vasodilation. Acta Physiol. Scand. 171, 9–16 (2001).

    CAS  PubMed  Google Scholar 

  298. Larsen, F. J., Ekblom, B., Sahlin, K., Lundberg, J. O. & Weitzberg, E. Effects of dietary nitrate on blood pressure in healthy volunteers. N. Engl. J. Med. 355, 2792–2793 (2006).

    Article  CAS  PubMed  Google Scholar 

  299. Kapil, V., Khambata, R. S., Robertson, A., Caulfield, M. J. & Ahluwalia, A. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension 65, 320–327 (2015).

    Article  CAS  PubMed  Google Scholar 

  300. Velmurugan, S. et al. Antiplatelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex. Free Radic. Biol. Med. 65, 1521–1532 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Webb, A. J. et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 51, 784–790 (2008).

    Article  CAS  PubMed  Google Scholar 

  302. Bhushan, S. et al. Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling. Circ. Res. 114, 1281–1291 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Duranski, M. R. et al. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. J. Clin. Invest. 115, 1232–1240 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Baker, J. E. et al. Nitrite confers protection against myocardial infarction: role of xanthine oxidoreductase, NADPH oxidase and K(ATP) channels. J. Mol. Cell. Cardiol. 43, 437–444 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. Webb, A. et al. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc. Natl Acad. Sci. USA 101, 13683–13688 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Rassaf, T. et al. Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning. Circ. Res. 114, 1601–1610 (2014).

    Article  CAS  PubMed  Google Scholar 

  307. Ingram, T. E. et al. Low-dose sodium nitrite attenuates myocardial ischemia and vascular ischemia-reperfusion injury in human models. J. Am. Coll. Cardiol. 61, 2534–2541 (2013).

    Article  CAS  PubMed  Google Scholar 

  308. Hendgen-Cotta, U. B. et al. Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc. Natl Acad. Sci. USA 105, 10256–10261 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  309. Hendgen-Cotta, U. B. et al. Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation 126, 1983–1992 (2012).

    Article  CAS  PubMed  Google Scholar 

  310. Borlaug, B. A. et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 56, 845–854 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  311. van Heerebeek, L. et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126, 830–839 (2012).

    Article  CAS  PubMed  Google Scholar 

  312. Borlaug, B. A., Koepp, K. E. & Melenovsky, V. Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 66, 1672–1682 (2015).

    Article  CAS  PubMed  Google Scholar 

  313. Zamani, P. et al. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation 131, 371–380 (2015).

    Article  CAS  PubMed  Google Scholar 

  314. Catry, E. et al. Targeting the gut microbiota with inulin-type fructans: preclinical demonstration of a novel approach in the management of endothelial dysfunction. Gut http://dx.doi.org/10.1136/gutjnl-2016-313316 (2017).

  315. Oller, J. et al. Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome. Nat. Med. 23, 200–212 (2017).

    Article  CAS  PubMed  Google Scholar 

  316. Shen, J. S. et al. Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease. Hum. Mol. Genet. 26, 1182–1192 (2017).

    Article  CAS  PubMed  Google Scholar 

  317. Galie, N. et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med. 353, 2148–2157 (2005).

    Article  CAS  PubMed  Google Scholar 

  318. Galie, N. et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 119, 2894–2903 (2009).

    Article  CAS  PubMed  Google Scholar 

  319. Shan, X. et al. Differential expression of PDE5 in failing and nonfailing human myocardium. Circ. Heart Fail. 5, 79–86 (2012).

    Article  CAS  PubMed  Google Scholar 

  320. Lu, Z. et al. Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation 121, 1474–1483 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  321. Salloum, F. N. et al. Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase G-dependent generation of hydrogen sulfide. Circulation 120, S31–36 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  322. Ahmad, N., Wang, Y., Ali, A. K. & Ashraf, M. Long-acting phosphodiesterase-5 inhibitor, tadalafil, induces sustained cardioprotection against lethal ischemic injury. Am. J. Physiol. Heart Circ. Physiol. 297, H387–H391 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  323. Andersen, M. J. et al. Sildenafil and diastolic dysfunction after acute myocardial infarction in patients with preserved ejection fraction: the Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction (SIDAMI) trial. Circulation 127, 1200–1208 (2013).

    Article  CAS  PubMed  Google Scholar 

  324. Takimoto, E. et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat. Med. 11, 214–222 (2005).

    Article  CAS  PubMed  Google Scholar 

  325. Takimoto, E. et al. Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J. Clin. Invest. 119, 408–420 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  326. Guazzi, M., Vicenzi, M., Arena, R. & Guazzi, M. D. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study. Circ. Heart Fail. 4, 8–17 (2011).

    Article  CAS  PubMed  Google Scholar 

  327. Lewis, G. D. et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 116, 1555–1562 (2007).

    Article  CAS  PubMed  Google Scholar 

  328. Guazzi, M., Tumminello, G., Di Marco, F., Fiorentini, C. & Guazzi, M. D. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J. Am. Coll. Cardiol. 44, 2339–2348 (2004).

    Article  CAS  PubMed  Google Scholar 

  329. Giannetta, E. et al. Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials. BMC Med. 12, 185 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  330. Guazzi, M., Vicenzi, M., Arena, R. & Guazzi, M. D. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation 124, 164–174 (2011).

    Article  CAS  PubMed  Google Scholar 

  331. Melenovsky, V., Hwang, S. J., Lin, G., Redfield, M. M. & Borlaug, B. A. Right heart dysfunction in heart failure with preserved ejection fraction. Eur. Heart J. 35, 3452–3462 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  332. Redfield, M. M. et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 309, 1268–1277 (2013).

    Article  CAS  PubMed  Google Scholar 

  333. Hoendermis, E. S. et al. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Eur. Heart J. 36, 2565–2573 (2015).

    Article  CAS  PubMed  Google Scholar 

  334. Borlaug, B. A. et al. Effects of sildenafil on ventricular and vascular function in heart failure with preserved ejection fraction. Circ. Heart Fail. 8, 533–541 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  335. Brutsaert, D. L. & De Keulenaer, G. W. Letter by Brutsaert and De Keulenaer regarding article, “Effects of sildenafil on ventricular and vascular function in heart failure with preserved ejection fraction”. Circ. Heart Fail. 8, 839 (2015).

    Article  PubMed  Google Scholar 

  336. Balligand, J. L. & Hammond, J. Protein kinase G type I in cardiac myocytes: unmasked at last? Eur. Heart J. 34, 1181–1185 (2013).

    Article  PubMed  Google Scholar 

  337. Tobler, D. et al. Effect of phosphodiesterase-5 inhibition with Tadalafil on SystEmic Right VEntricular size and function - A multi-center, double-blind, randomized, placebo-controlled clinical trial — SERVE trial — Rational and design. Int. J. Cardiol. 243, 354–359 (2017).

    Article  PubMed  Google Scholar 

  338. Ko, F. N., Wu, C. C., Kuo, S. C., Lee, F. Y. & Teng, C. M. YC-1, a novel activator of platelet guanylate cyclase. Blood 84, 4226–4233 (1994).

    CAS  PubMed  Google Scholar 

  339. Stasch, J. P. et al. NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle. Br. J. Pharmacol. 136, 773–783 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  340. Gheorghiade, M. et al. Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes. Eur. J. Heart Fail. 14, 1056–1066 (2012).

    Article  CAS  PubMed  Google Scholar 

  341. Erdmann, E. et al. Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure. Eur. Heart J. 34, 57–67 (2013).

    Article  CAS  PubMed  Google Scholar 

  342. Ghofrani, H. A. et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N. Engl. J. Med. 369, 319–329 (2013).

    Article  CAS  PubMed  Google Scholar 

  343. Rubin, L. J. et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur. Respir. J. 45, 1303–1313 (2015).

    Article  CAS  PubMed  Google Scholar 

  344. Simonneau, G. et al. Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN. Eur. Respir. J. 46, 1711–1720 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  345. Bonderman, D. et al. Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study. Chest 146, 1274–1285 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  346. Bonderman, D. et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation 128, 502–511 (2013).

    Article  CAS  PubMed  Google Scholar 

  347. Gheorghiade, M. et al. Effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction: the SOCRATES-REDUCED randomized trial. JAMA 314, 2251–2262 (2015).

    Article  CAS  PubMed  Google Scholar 

  348. Pieske, B. et al. Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES). Eur. J. Heart Fail. 16, 1026–1038 (2014).

    Article  CAS  PubMed  Google Scholar 

  349. Pieske, B. et al. Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur. Heart J. 38, 1119–1127 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  350. Heitzer, T., Krohn, K., Albers, S. & Meinertz, T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia 43, 1435–1438 (2000).

    Article  CAS  PubMed  Google Scholar 

  351. Porkert, M. et al. Tetrahydrobiopterin: a novel antihypertensive therapy. J. Hum. Hypertens. 22, 401–407 (2008).

    Article  CAS  PubMed  Google Scholar 

  352. Cunnington, C. et al. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease. Circulation 125, 1356–1366 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  353. Hao, L. et al. Folate status and homocysteine response to folic acid doses and withdrawal among young Chinese women in a large-scale randomized double-blind trial. Am. J. Clin. Nutr. 88, 448–457 (2008).

    Article  CAS  PubMed  Google Scholar 

  354. Gao, L., Chalupsky, K., Stefani, E. & Cai, H. Mechanistic insights into folic acid-dependent vascular protection: dihydrofolate reductase (DHFR)-mediated reduction in oxidant stress in endothelial cells and angiotensin II-infused mice: a novel HPLC-based fluorescent assay for DHFR activity. J. Mol. Cell. Cardiol. 47, 752–760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  355. Crabtree, M. J. & Channon, K. M. Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide 25, 81–88 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  356. Joshi, R., Adhikari, S., Patro, B. S., Chattopadhyay, S. & Mukherjee, T. Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radic. Biol. Med. 30, 1390–1399 (2001).

    Article  CAS  PubMed  Google Scholar 

  357. Antoniades, C. et al. 5-Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation 114, 1193–1201 (2006).

    Article  CAS  PubMed  Google Scholar 

  358. Chalupsky, K., Kracun, D., Kanchev, I., Bertram, K. & Gorlach, A. Folic acid promotes recycling of tetrahydrobiopterin and protects against hypoxia-induced pulmonary hypertension by recoupling endothelial nitric oxide synthase. Antioxid. Redox Signal. 23, 1076–1091 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  359. Shirodaria, C. et al. Global improvement of vascular function and redox state with low-dose folic acid: implications for folate therapy in patients with coronary artery disease. Circulation 115, 2262–2270 (2007).

    Article  CAS  PubMed  Google Scholar 

  360. Doshi, S. N. et al. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation 105, 22–26 (2002).

    Article  CAS  PubMed  Google Scholar 

  361. Tucker, K. L., Mahnken, B., Wilson, P. W., Jacques, P. & Selhub, J. Folic acid fortification of the food supply. Potential benefits and risks for the elderly population. JAMA 276, 1879–1885 (1996).

    Article  CAS  PubMed  Google Scholar 

  362. Gori, T. et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation 104, 1119–1123 (2001).

    Article  CAS  PubMed  Google Scholar 

  363. Title, L. M., Cummings, P. M., Giddens, K., Genest, J. J. Jr & Nassar, B. A. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J. Am. Coll. Cardiol. 36, 758–765 (2000).

    Article  CAS  PubMed  Google Scholar 

  364. Bonaa, K. H. et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N. Engl. J. Med. 354, 1578–1588 (2006).

    Article  CAS  PubMed  Google Scholar 

  365. Albert, C. M. et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 299, 2027–2036 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  366. Li, Y. et al. Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J. Am. Heart Assoc. 5, e003768 (2016).

    PubMed  PubMed Central  Google Scholar 

  367. Mason, J. B. et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol. Biomarkers Prev. 16, 1325–1329 (2007).

    Article  CAS  PubMed  Google Scholar 

  368. Qin, X. et al. Effect of folic acid supplementation on cancer risk among adults with hypertension in China: a randomized clinical trial. Int. J. Cancer 141, 837–847 (2017).

    Article  CAS  PubMed  Google Scholar 

  369. Hubner, R. A., Houlston, R. D. & Muir, K. R. Should folic acid fortification be mandatory? No. BMJ 334, 1253 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  370. Boslett, J., Hemann, C., Zhao, Y. J., Lee, H. C. & Zweier, J. L. Luteolinidin protects the postischemic heart through CD38 inhibition with preservation of NAD(P)(H). J. Pharmacol. Exp. Ther. 361, 99–108 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  371. Moccia, F. et al. Hydrogen sulfide regulates intracellular Ca2+ concentration in endothelial cells from excised rat aorta. Curr. Pharm. Biotechnol. 12, 1416–1426 (2011).

    Article  CAS  PubMed  Google Scholar 

  372. Altaany, Z., Yang, G. & Wang, R. Crosstalk between hydrogen sulfide and nitric oxide in endothelial cells. J. Cell. Mol. Med. 17, 879–888 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  373. Bir, S. C. et al. Hydrogen sulfide stimulates ischemic vascular remodeling through nitric oxide synthase and nitrite reduction activity regulating hypoxia-inducible factor-1alpha and vascular endothelial growth factor-dependent angiogenesis. J. Am. Heart Assoc. 1, e004093 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  374. Nishida, M. et al. Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration. Nat. Chem. Biol. 8, 714–724 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  375. Predmore, B. L. et al. The polysulfide diallyl trisulfide protects the ischemic myocardium by preservation of endogenous hydrogen sulfide and increasing nitric oxide bioavailability. Am. J. Physiol. Heart Circ. Physiol. 302, H2410–H2418 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  376. Polhemus, D. et al. Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ. Heart Fail. 6, 1077–1086 (2013).

    Article  CAS  PubMed  Google Scholar 

  377. Elrod, J. W. et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc. Natl Acad. Sci. USA 104, 15560–15565 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  378. Hayashida, R. et al. Diallyl trisulfide augments ischemia-induced angiogenesis via an endothelial nitric oxide synthase-dependent mechanism. Circ. J. 81, 870–878 (2017).

    Article  CAS  PubMed  Google Scholar 

  379. Kang, J. et al. pH-controlled hydrogen sulfide release for myocardial ischemia-reperfusion injury. J. Am. Chem. Soc. 138, 6336–6339 (2016).

    Article  CAS  PubMed  Google Scholar 

  380. Polhemus, D. J. et al. A novel hydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric oxide bioavailability in heart failure patients. Cardiovasc. Ther. 33, 216–226 (2015).

    Article  CAS  PubMed  Google Scholar 

  381. Hu, Q. et al. Novel angiogenic activity and molecular mechanisms of ZYZ-803, a slow-releasing hydrogen sulfide-nitric oxide hybrid molecule. Antioxid. Redox Signal. 25, 498–514 (2016).

    Article  CAS  PubMed  Google Scholar 

  382. Pufahl, R. A., Wishnok, J. S. & Marletta, M. A. Hydrogen peroxide-supported oxidation of NG-hydroxy-L-arginine by nitric oxide synthase. Biochemistry 34, 1930–1941 (1995).

    Article  CAS  PubMed  Google Scholar 

  383. Adak, S., Wang, Q. & Stuehr, D. J. Arginine conversion to nitroxide by tetrahydrobiopterin-free neuronal nitric-oxide synthase. Implications for mechanism. J. Biol. Chem. 275, 33554–33561 (2000).

    Article  CAS  PubMed  Google Scholar 

  384. Woodward, J. J., Nejatyjahromy, Y., Britt, R. D. & Marletta, M. A. Pterin-centered radical as a mechanistic probe of the second step of nitric oxide synthase. J. Am. Chem. Soc. 132, 5105–5113 (2010).

    Article  CAS  PubMed  Google Scholar 

  385. Katori, T. et al. Peroxynitrite and myocardial contractility: in vivo versus in vitro effects. Free Radic. Biol. Med. 41, 1606–1618 (2006).

    Article  CAS  PubMed  Google Scholar 

  386. Paolocci, N. et al. Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: independence from beta-adrenergic signaling. Proc. Natl Acad. Sci. USA 100, 5537–5542 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  387. Tocchetti, C. G. et al. Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling. Circ. Res. 100, 96–104 (2007).

    Article  CAS  PubMed  Google Scholar 

  388. Ding, W. et al. Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca2+. J. Pharmacol. Exp. Ther. 339, 825–831 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  389. Gao, W. D. et al. Nitroxyl-mediated disulfide bond formation between cardiac myofilament cysteines enhances contractile function. Circ. Res. 111, 1002–1011 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  390. Froehlich, J. P. et al. Phospholamban thiols play a central role in activation of the cardiac muscle sarcoplasmic reticulum calcium pump by nitroxyl. Biochemistry 47, 13150–13152 (2008).

    Article  CAS  PubMed  Google Scholar 

  391. Sivakumaran, V. et al. HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization. Antioxid. Redox Signal. 19, 1185–1197 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  392. Tocchetti, C. G. et al. Playing with cardiac “redox switches”: the “HNO way” to modulate cardiac function. Antioxid. Redox Signal. 14, 1687–1698 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  393. Sabbah, H. N. et al. Nitroxyl (HNO): a novel approach for the acute treatment of heart failure. Circ. Heart Fail. 6, 1250–1258 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  394. Zhu, G. et al. Soluble guanylate cyclase is required for systemic vasodilation but not positive inotropy induced by nitroxyl in the mouse. Hypertension 65, 385–392 (2015).

    Article  CAS  PubMed  Google Scholar 

  395. Tita, C. et al. A phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction. Eur. J. Heart Fail. 19, 1321–1332 (2017).

    Article  CAS  PubMed  Google Scholar 

  396. Siddiqi, N. et al. Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI). Eur. Heart J. 35, 1255–1262 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  397. Jones, D. A. et al. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Circ. Res. 116, 437–447 (2015).

    Article  CAS  PubMed  Google Scholar 

  398. Borlaug, B. A., Melenovsky, V. & Koepp, K. E. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ. Res. 119, 880–886 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  399. Eggebeen, J. et al. One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. JACC Heart Fail. 4, 428–437 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  400. Reddy, Y. N. V. et al. INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): rationale and design. Circ. Heart Fail. 10, e003862 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  401. Simon, M. A. et al. Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight 1, e89620 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  402. Montenegro, M. F. et al. Blood pressure-lowering effect of orally ingested nitrite is abolished by a proton pump inhibitor. Hypertension 69, 23–31 (2017).

    Article  CAS  PubMed  Google Scholar 

  403. Hughan, K. S. et al. Conjugated linoleic acid modulates clinical responses to oral nitrite and nitrate. Hypertension 70, 634–644 (2017).

    Article  CAS  PubMed  Google Scholar 

  404. Nantel, F. et al. The human beta 3-adrenergic receptor is resistant to short term agonist-promoted desensitization. Mol. Pharmacol. 43, 548–555 (1993).

    CAS  PubMed  Google Scholar 

  405. Moniotte, S. et al. Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation 103, 1649–1655 (2001).

    Article  CAS  PubMed  Google Scholar 

  406. Dessy, C. et al. Endothelial beta3-adrenoceptors mediate vasorelaxation of human coronary microarteries through nitric oxide and endothelium-dependent hyperpolarization. Circulation 110, 948–954 (2004).

    Article  CAS  PubMed  Google Scholar 

  407. Vij, M. & Drake, M. J. Clinical use of the beta3 adrenoceptor agonist mirabegron in patients with overactive bladder syndrome. Ther. Adv. Urol. 7, 241–248 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  408. Bundgaard, H. et al. The-first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT-HF trial. Eur. J. Heart Fail. 19, 566–575 (2017).

    Article  CAS  PubMed  Google Scholar 

  409. Balligand, J. L. Cardiac beta3-adrenergic receptors in the clinical arena: the end of the beginning. Eur. J. Heart Fail. 19, 576–578 (2017).

    Article  PubMed  Google Scholar 

  410. Garcia-Alvarez, A. et al. Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension. Bas. Res. Cardiol. 111, 49 (2016).

    Article  CAS  Google Scholar 

  411. Karimi Galougahi, K. et al. Beta3 adrenergic stimulation restores nitric oxide/redox balance and enhances endothelial function in hyperglycemia. J. Am. Heart Assoc. 5, e002824 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  412. Garlichs, C. D. et al. Decreased plasma concentrations of L-hydroxy-arginine as a marker of reduced NO formation in patients with combined cardiovascular risk factors. J. Lab. Clin. Med. 135, 419–425 (2000).

    Article  CAS  PubMed  Google Scholar 

  413. Henry, Y. & Banerjee, R. Electron paramagnetic studies of nitric oxide haemoglobin derivatives: isolated subunits and nitric oxide hybrids. J. Mol. Biol. 73, 469–482 (1973).

    Article  CAS  PubMed  Google Scholar 

  414. Hamburg, N. M. et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation 117, 2467–2474 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  415. Nakayama, M. et al. T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 99, 2864–2870 (1999).

    Article  CAS  PubMed  Google Scholar 

  416. Miyamoto, Y. et al. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T→C mutation associated with coronary spastic angina. Hum. Mol. Genet. 9, 2629–2637 (2000).

    Article  CAS  PubMed  Google Scholar 

  417. Rai, H., Parveen, F., Kumar, S., Kapoor, A. & Sinha, N. Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review. PLoS ONE 9, e113363 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  418. Sandrim, V. C. et al. Susceptible and protective eNOS haplotypes in hypertensive black and white subjects. Atherosclerosis 186, 428–432 (2006).

    Article  CAS  PubMed  Google Scholar 

  419. Serrano, N. C. et al. Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study. Hypertension 44, 702–707 (2004).

    Article  CAS  PubMed  Google Scholar 

  420. Safarinejad, M. R., Khoshdel, A., Shekarchi, B., Taghva, A. & Safarinejad, S. Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects. BJU Int. 107, 1994–2001 (2011).

    Article  CAS  PubMed  Google Scholar 

  421. Salvi, E. et al. Target sequencing, cell experiments, and a population study establish endothelial nitric oxide synthase (eNOS) gene as hypertension susceptibility gene. Hypertension 62, 844–852 (2013).

    Article  CAS  PubMed  Google Scholar 

  422. Nelson, C. P. et al. Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nat. Genet. 49, 1385–1391 (2017).

    Article  CAS  PubMed  Google Scholar 

  423. Nikpay, M. et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat. Genet. 47, 1121–1130 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  424. Johnson, T. et al. Blood pressure loci identified with a gene-centric array. Am. J. Hum. Genet. 89, 688–700 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  425. Zhang, M. X. et al. Regulation of endothelial nitric oxide synthase by small RNA. Proc. Natl Acad. Sci. USA 102, 16967–16972 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  426. Zhang, M. X. et al. Effect of 27nt small RNA on endothelial nitric-oxide synthase expression. Mol. Biol. Cell 19, 3997–4005 E07-11-1186 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  427. Casas, J. P., Bautista, L. E., Humphries, S. E. & Hingorani, A. D. Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects. Circulation 109, 1359–1365 (2004).

    Article  CAS  PubMed  Google Scholar 

  428. Galanakis, E. et al. Intron 4 a/b polymorphism of the endothelial nitric oxide synthase gene is associated with both type 1 and type 2 diabetes in a genetically homogeneous population. Hum. Immunol. 69, 279–283 (2008).

    Article  CAS  PubMed  Google Scholar 

  429. Mehrab-Mohseni, M. et al. Endothelial nitric oxide synthase VNTR (intron 4 a/b) polymorphism association with type 2 diabetes and its chronic complications. Diabetes Res. Clin. Practice 91, 348–352 (2011).

    Article  CAS  Google Scholar 

  430. Joshi, M. S., Mineo, C., Shaul, P. W. & Bauer, J. A. Biochemical consequences of the NOS3 Glu298Asp variation in human endothelium: altered caveolar localization and impaired response to shear. FASEB J. 21, 2655–2663 (2007).

    Article  CAS  PubMed  Google Scholar 

  431. Antoniades, C. et al. Genetic polymorphism on endothelial nitric oxide synthase affects endothelial activation and inflammatory response during the acute phase of myocardial infarction. J. Am. Coll. Cardiol. 46, 1101–1109 (2005).

    Article  CAS  PubMed  Google Scholar 

  432. Shimasaki, Y. et al. Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J. Am. Coll. Cardiol. 31, 1506–1510 (1998).

    Article  CAS  PubMed  Google Scholar 

  433. Colombo, M. G. et al. Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298→Asp polymorphism) to the presence, extent, and severity of coronary artery disease. Heart 87, 525–528 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  434. Lee, Y. C. et al. The associations among eNOS G894T gene polymorphism, erectile dysfunction, and benign prostate hyperplasia-related lower urinary tract symptoms. J. Sexual Med. 6, 3158–3165 (2009).

    Article  CAS  Google Scholar 

  435. Kessler, T. et al. Functional characterization of the GUCY1A3 coronary artery disease risk locus. Circulation 136, 476–489 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  436. Erdmann, J. et al. Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 504, 432–436 (2013).

    Article  CAS  PubMed  Google Scholar 

  437. Ding, H. et al. A novel loss-of-function DDAH1 promoter polymorphism is associated with increased susceptibility to thrombosis stroke and coronary heart disease. Circ. Res. 106, 1145–1152 (2010).

    Article  CAS  PubMed  Google Scholar 

  438. Yang, Z. et al. Identification of a novel polymorphism in the 3′UTR of the L-arginine transporter gene SLC7A1: contribution to hypertension and endothelial dysfunction. Circulation 115, 1269–1274 (2007).

    Article  CAS  PubMed  Google Scholar 

  439. Guo, D. C. et al. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am. J. Hum. Genet. 93, 398–404 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  440. Ganesh, S. K. et al. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Hum. Mol. Genet. 22, 1663–1678 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  441. The International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103–109 (2011).

  442. Ehret, G. B. et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat. Genet. 48, 1171–1184 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  443. Liu, C. et al. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. Nat. Genet. 48, 1162–1170 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  444. Kato, N. et al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation. Nat. Genet. 47, 1282–1293 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  445. Warren, H. R. et al. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat. Genet. 49, 403–415 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  446. Wild, P. S. et al. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. J. Clin. Invest. 127, 1798–1812 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  447. Vasan, R. S. et al. Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. JAMA 302, 168–178 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  448. Newton-Cheh, C. et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399–406 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  449. Pfeufer, A. et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41, 407–414 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  450. Jamshidi, Y. et al. Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia. J. Am. Coll. Cardiol. 60, 841–850 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  451. Kao, W. H. et al. Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. Circulation 119, 940–951 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  452. Eijgelsheim, M. et al. Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study. Hum. Mol. Genet. 18, 4213–4218 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  453. Yin, C., Salloum, F. N. & Kukreja, R. C. A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70. Circ. Res. 104, 572–575 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  454. Meloni, M. et al. Local inhibition of microRNA-24 improves reparative angiogenesis and left ventricle remodeling and function in mice with myocardial infarction. Mol. Ther. 21, 1390–1402 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  455. Sun, H. X. et al. Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension 60, 1407–1414 (2012).

    Article  CAS  PubMed  Google Scholar 

  456. Zhang, J., Zhao, F., Yu, X., Lu, X. & Zheng, G. MicroRNA-155 modulates the proliferation of vascular smooth muscle cells by targeting endothelial nitric oxide synthase. Int. J. Mol. Med. 35, 1708–1714 (2015).

    Article  CAS  PubMed  Google Scholar 

  457. Fichtlscherer, S. et al. Circulating microRNAs in patients with coronary artery disease. Circ. Res. 107, 677–684 (2010).

    Article  CAS  PubMed  Google Scholar 

  458. Magenta, A. et al. miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ. 18, 1628–1639 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  459. Carlomosti, F. et al. Oxidative stress-induced miR-200c disrupts the regulatory loop among SIRT1, FOXO1, and eNOS. Antioxid. Redox Signal. 27, 328–344 (2017).

    Article  CAS  PubMed  Google Scholar 

  460. Ho, J. J. et al. Active stabilization of human endothelial nitric oxide synthase mRNA by hnRNP E1 protects against antisense RNA and microRNAs. Mol. Cell. Biol. 33, 2029–2046 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  461. Fish, J. E. et al. Hypoxia-inducible expression of a natural cis-antisense transcript inhibits endothelial nitric-oxide synthase. J. Biol. Chem. 282, 15652–15666 (2007).

    Article  CAS  PubMed  Google Scholar 

  462. Meng, F. et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133, 647–658 (2007).

    Article  CAS  PubMed  Google Scholar 

  463. Weber, M., Baker, M. B., Moore, J. P. & Searles, C. D. MiR-21 is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity. Biochem. Biophys. Res. Commun. 393, 643–648 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  464. Zhou, J. et al. MicroRNA-21 targets peroxisome proliferators-activated receptor-alpha in an autoregulatory loop to modulate flow-induced endothelial inflammation. Proc. Natl Acad. Sci. USA 108, 10355–10360 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  465. Cengiz, M. et al. Circulating miR-21 and eNOS in subclinical atherosclerosis in patients with hypertension. Clin. Exp. Hypertens. 37, 643–649 (2015).

    Article  CAS  PubMed  Google Scholar 

  466. Fang, Y. & Davies, P. F. Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler. Thromb. Vasc. Biol. 32, 979–987 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  467. Chiplunkar, A. R. et al. The Kruppel-like factor 2 and Kruppel-like factor 4 genes interact to maintain endothelial integrity in mouse embryonic vasculogenesis. BMC Dev. Biol. 13, 40 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  468. Wu, W. et al. Flow-dependent regulation of Kruppel-like factor 2 is mediated by microRNA-92a. Circulation 124, 633–641 (2011).

    Article  CAS  PubMed  Google Scholar 

  469. Loyer, X. et al. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ. Res. 114, 434–443 (2014).

    Article  CAS  PubMed  Google Scholar 

  470. Chen, Z. et al. Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a. Circulation 131, 805–814 (2015).

    Article  CAS  PubMed  Google Scholar 

  471. Bonauer, A. et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324, 1710–1713 (2009).

    Article  CAS  PubMed  Google Scholar 

  472. Li, P. et al. Inhibition of aberrant microRNA-133a expression in endothelial cells by statin prevents endothelial dysfunction by targeting GTP cyclohydrolase 1 in vivo. Circulation 134, 1752–1765 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  473. Vikram, A. et al. Vascular microRNA-204 is remotely governed by the microbiome and impairs endothelium-dependent vasorelaxation by downregulating sirtuin1. Nat. Commun. 7, 12565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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All authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

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Correspondence to Jean-Luc Balligand.

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Farah, C., Michel, L. & Balligand, JL. Nitric oxide signalling in cardiovascular health and disease. Nat Rev Cardiol 15, 292–316 (2018). https://doi.org/10.1038/nrcardio.2017.224

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