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  • Review Article
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The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis

Nature Reviews Drug Discovery volume 10, pages 277–291 (2011)Cite this article

Subjects

Key Points

  • Asymmetrically methylated arginines — principally asymmetric dimethylarginine (ADMA; that is, ω-NG,NG-asymmetric dimethylargenine) — are endogenously produced competitive inhibitors of nitric oxide synthase (NOS) enzymes. The concentration of asymmetric methylarginines is actively regulated in vivo by the action of dimethylarginine dimethylaminohydrolase (DDAH) enzymes that metabolize methylarginines to L-citrulline and methylamine.

  • Modulation of DDAH activity in experimental models has demonstrated that endogenous inhibitors of NOS tonically inhibit the basal activity of NOS. Genetic or pharmacological disruption of DDAH activity impairs cardiovascular homeostasis in vivo, whereas overexpression of DDAH protects against cardiovascular disease in model systems.

  • Genetic polymorphisms in human DDAH genes are associated with a variation in circulating ADMA levels and disease progression in several cardiovascular diseases including stroke, thrombosis and coronary artery disease. Increases in circulating plasma ADMA concentrations have been shown to strongly predict mortality in patients with end-stage renal disease.

  • Pharmacological elevation of ADMA concentration has been suggested to be therapeutically useful in disease states in which excessive NO synthesis contributes to disease (for example, septic shock). Consistent with this proposition, genetic or pharmacological inhibition of DDAH has been shown to attenuate NO-dependent hypotension that is induced in animals with sepsis.

Abstract

Asymmetric dimethylarginine (ADMA) — a naturally occurring amino acid that is a product of protein breakdown — is released into the cytoplasm following the post-translational methylation of arginine residues within proteins and the subsequent proteolysis of these arginine-methylated proteins. ADMA inhibits all three isoforms of nitric oxide synthase and therefore has the potential to produce diverse biological effects, particularly in the cardiovascular system. In addition to its renal clearance, endogenously produced ADMA is metabolized to L-citrulline and dimethylamine by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Pharmacological modification of DDAH has therefore been proposed as a mechanism for manipulating endogenous ADMA concentrations and regulating the production of nitric oxide in situations where alterations in nitric oxide signalling have been shown to contribute to pathophysiology. This Review describes the biology of ADMA and the potential therapeutic utility of manipulating DDAH activity.

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Figure 1: The ADMA–DDAH–NOS pathway.
Figure 2: Endogenous synthesis of methylarginines.
Figure 3: Small-molecule inhibitors of DDAH.

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References

  1. Paik, W. K. & Kim, S. Enzymatic methylation of protein fractions from calf thymus nuclei. Biochem. Biophys. Res. Commun. 29, 14–20 (1967).

    Article  CAS  PubMed  Google Scholar 

  2. Gary, J. D. & Clarke, S. RNA and protein interactions modulated by protein arginine methylation. Prog. Nucleic Acid Res. Mol. Biol. 61, 65–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Kakimoto, Y. & Akazawa, S. Isolation and identification of NG,NG- and NG,N′G-dimethyl-arginine, Nɛ-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-δ-hydroxylysine from human urine. J. Biol. Chem. 245, 5751–578 (1970).

    CAS  PubMed  Google Scholar 

  4. Closs, E. I., Basha, F. Z., Habermeier, A. & Forstermann, U. Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide 1, 65–73 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Tsikas, D., Boger, R. H., Sandmann, J., Bode-Boger, S. M. & Frolich, J. C. Endogenous nitric oxide synthase inhibitors are responsible for the L-arginine paradox. FEBS Lett. 478, 1–3 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Vallance, P., Leone, A., Calver, A., Collier, J. & Moncada, S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339, 572–575 (1992). The first report to show that endogenous inhibitors of NO synthesis accumulated in a human disease state in which reduced NO synthesis was implicated in disease progression.

    Article  CAS  PubMed  Google Scholar 

  7. Ogawa, T., Kimoto, M. & Sasaoka, K. Purification and properties of a new enzyme, NG,NG-dimethylarginine dimethylaminohydrolase, from rat kidney. J. Biol. Chem. 264, 10205–10209 (1989).

    CAS  PubMed  Google Scholar 

  8. Valkonen, V. P. et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 358, 2127–1218 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Stuhlinger, M. C. et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287, 1420–1426 (2002).

    Article  PubMed  Google Scholar 

  10. Schnabel, R. et al. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ. Res. 97, e53–e59 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Zoccali, C. Asymmetric dimethylarginine (ADMA): a cardiovascular and renal risk factor on the move. J. Hypertens. 24, 611–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Thiemermann, C. The role of the L-arginine: nitric oxide pathway in circulatory shock. Adv. Pharmacol. 28, 45–79 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Dulak, J. & Jozkowicz, A. Regulation of vascular endothelial growth factor synthesis by nitric oxide: facts and controversies. Antioxid. Redox Signal. 5, 123–132 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Cuzzocrea, S. et al. Beneficial effects of GW274150, a novel, potent and selective inhibitor of iNOS activity, in a rodent model of collagen-induced arthritis. Eur. J. Pharmacol. 453, 119–129 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Thomsen, L. L. & Miles, D. W. Role of nitric oxide in tumour progression: lessons from human tumours. Cancer Metastasis Rev. 17, 107–118 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Mocellin, S., Bronte, V. & Nitti, D. Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities. Med. Res. Rev. 27, 317–352 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Hollenberg, S. M. & Cinel, I. Bench-to-bedside review: nitric oxide in critical illness — update 2008. Crit. Care 13, 218 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang, R., Ma, A., Urbanski, S. J. & McCafferty, D. M. Induction of inducible nitric oxide synthase: a protective mechanism in colitis-induced adenocarcinoma. Carcinogenesis 28, 1122–1230 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Vincent, J. L., Zhang, H., Szabo, C. & Preiser, J. C. Effects of nitric oxide in septic shock. Am. J. Respir. Crit. Care Med. 161, 1781–1785 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Wink, D. A., Ridnour, L. A., Hussain, S. P. & Harris, C. C. The re-emergence of nitric oxide and cancer. Nitric Oxide 19, 65–67 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wahl, S. M. et al. Nitric oxide in experimental joint inflammation. Benefit or detriment? Cells Tissues Organs 174, 26–33 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Alderton, W. K., Cooper, C. E. & Knowles, R. G. Nitric oxide synthases: structure, function and inhibition. Biochem. J. 357, 593–615 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. MacAllister, R. J., Fickling, S. A., Whitley, G. S. & Vallance, P. Metabolism of methylarginines by human vasculature; implications for the regulation of nitric oxide synthesis. Br. J. Pharmacol. 112, 43–48 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Achan, V. et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler. Thromb. Vasc. Biol. 23, 1455–1459 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Kielstein, J. T. et al. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 109, 172–177 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Cardounel, A. J. et al. Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J. Biol. Chem. 282, 879–887 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Maxwell, A. J., Anderson, B., Zapien, M. P. & Cooke, J. P. Endothelial dysfunction in hypercholesterolemia is reversed by a nutritional product designed to enhance nitric oxide activity. Cardiovasc. Drugs Ther. 14, 309–316 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Boger, R. H. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “L-arginine paradox” and acts as a novel cardiovascular risk factor. J. Nutr. 134, 2842S–2847S; Comments 2853S (2004).

    Article  PubMed  Google Scholar 

  29. Clarke, S. Protein methylation. Curr. Opin. Cell Biol. 5, 977–983 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Aletta, J. M., Cimato, T. R. & Ettinger, M. J. Protein methylation: a signal event in post-translational modification. Trends Biochem. Sci. 23, 89–91 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Katz, J. E., Dlakic, M. & Clarke, S. Automated identification of putative methyltransferases from genomic open reading frames. Mol. Cell Proteomics 2, 525–540 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Miyake, M. & Kakimoto, Y. Synthesis and degradation of methylated proteins of mouse organs: correlation with protein synthesis and degradation. Metabolism 25, 885–896 (1976).

    Article  CAS  PubMed  Google Scholar 

  33. Pawlak, M. R., Scherer, C. A., Chen, J., Roshon, M. J. & Ruley, H. E. Arginine N-methyltransferase 1 is required for early postimplantation mouse development, but cells deficient in the enzyme are viable. Mol. Cell Biol. 20, 4859–4869 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Krause, C. D. et al. Protein arginine methyltransferases: evolution and assessment of their pharmacological and therapeutic potential. Pharmacol. Ther. 113, 50–87 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Ogawa, T., Kimoto, M. & Sasaoka, K. Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats. Biochem. Biophys. Res. Commun. 148, 671–677 (1987). This paper describes the identification of DDAH, which is the major endogenous enzyme for the metabolism of endogenously produced NOS inhibitors.

    Article  CAS  PubMed  Google Scholar 

  36. Ogawa, T., Kimoto, M. & Sasaoka, K. Dimethylarginine: pyruvate aminotransferase in rats. Purification, properties, and identity with alanine: glyoxylate aminotransferase 2. J. Biol. Chem. 265, 20938–20945 (1990).

    CAS  PubMed  Google Scholar 

  37. Rodionov, R. N., Murry, D. J., Vaulman, S. F., Stevens, J. W. & Lentz, S. R. Human alanine-glyoxylate aminotransferase 2 lowers asymmetric dimethylarginine and protects from inhibition of nitric oxide production. J. Biol. Chem. 285, 5385–5391 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Kimoto, M., Tsuji, H., Ogawa, T. & Sasaoka, K. Detection of NG,NG-dimethylarginine dimethylaminohydrolase in the nitric oxide-generating systems of rats using monoclonal antibody. Arch. Biochem. Biophys. 300, 657–662 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Leiper, J. et al. Disruption of methylarginine metabolism impairs vascular homeostasis. Nature Med. 13, 198–203 (2007). The first demonstration of a causal relationship between elevation of endogenous NOS inhibitors and cardiovascular dysfunction. This work also demonstrated the therapeutic potential of targeting the DDAH–ADMA–NOS axis in disease states in which overproduction of NO contributes to pathology.

    Article  CAS  PubMed  Google Scholar 

  40. Leiper, J. M. et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem. J. 343, 209–214 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tran, C. T., Fox, M. F., Vallance, P. & Leiper, J. M. Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics 68, 101–105 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Tojo, A. et al. Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int. 52, 1593–1601 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Arrigoni, F. I., Vallance, P., Haworth, S. G. & Leiper, J. M. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation 107, 1195–1201 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. MacAllister, R. J. et al. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br. J. Pharmacol. 119, 1533–1540 (1996). The first description of the effects of impaired methylarginine metabolism on vascular NO synthesis and vascular responses. This work also identified the first selective inhibitor of DDAH activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, D. et al. Isoform-specific regulation by NG,NG-dimethylarginine dimethylaminohydrolase of rat serum asymmetric dimethylarginine and vascular endothelium-derived relaxing factor/NO. Circ. Res. 101, 627–635 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Pope, A. J., Karrupiah, K., Kearns, P. N., Xia, Y. & Cardounel, A. J. Role of dimethylarginine dimethylaminohydrolases in the regulation of endothelial nitric oxide production. J. Biol. Chem. 284, 35338–35347 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Feng, M., Liu, L., Guo, Z. & Xiong, Y. Gene transfer of dimethylarginine dimethylaminohydrolase-2 improves the impairments of DDAH/ADMA/NOS/NO pathway in endothelial cells induced by lysophosphatidylcholine. Eur. J. Pharmacol. 584, 49–56 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Lu, C. W. et al. Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells. Atherosclerosis 209, 66–73 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Hasegawa, K. et al. Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2. Circ. Res. 101, e2–e10 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Feng, M. et al. Improvement of endothelial dysfunction in atherosclerotic rabbit aortas by ex vivo gene transferring of dimethylarginine dimethylaminohydrolase-2. Int. J. Cardiol. 144, 180–186 (2010).

    Article  PubMed  Google Scholar 

  51. Hasegawa, K. et al. Dimethylarginine dimethylaminohydrolase 2 increases vascular endothelial growth factor expression through Sp1 transcription factor in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 26, 1488–1494 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Torondel, B. et al. Adenoviral-mediated overexpression of DDAH improves vascular tone regulation. Vasc. Med. 15, 205–213 (2010).

    Article  PubMed  Google Scholar 

  53. Smith, C. L. et al. Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype. Biochem. Biophys. Res. Commun. 308, 984–989 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Abhary, S. et al. Sequence variation in DDAH1 and DDAH2 genes is strongly and additively associated with serum ADMA concentrations in individuals with type 2 diabetes. PLoS ONE 5, e9462 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Perticone, F. et al. Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension. J. Am. Coll. Cardiol. 46, 518–523 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Stuhlinger, M. C. et al. Asymmetric dimethyl L-arginine (ADMA) is a critical regulator of myocardial reperfusion injury. Cardiovasc. Res. 75, 417–425 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Vladimirova-Kitova, L. et al. Relationship of asymmetric dimethylarginine with flow-mediated dilatation in subjects with newly detected severe hypercholesterolemia. Clin. Physiol. Funct. Imaging 28, 417–425 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Boger, R. H., Maas, R., Schulze, F. & Schwedhelm, E. Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality — an update on patient populations with a wide range of cardiovascular risk. Pharmacol. Res. 60, 481–487 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Nicholls, S. J. et al. Metabolic profiling of arginine and nitric oxide pathways predicts hemodynamic abnormalities and mortality in patients with cardiogenic shock after acute myocardial infarction. Circulation 116, 2315–2324 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Skoro-Sajer, N. et al. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am. J. Respir. Crit. Care Med. 176, 1154–1160 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Juonala, M. et al. Brachial artery flow-mediated dilation and asymmetrical dimethylarginine in the cardiovascular risk in young Finns study. Circulation 116, 1367–1373 (2007).

    Article  PubMed  Google Scholar 

  62. Duckelmann, C. et al. Asymmetric dimethylarginine enhances cardiovascular risk prediction in patients with chronic heart failure. Arterioscler. Thromb. Vasc. Biol. 27, 2037–2042 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Melikian, N. et al. Asymmetric dimethylarginine and reduced nitric oxide bioavailability in young Black African men. Hypertension 49, 873–877 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Mittermayer, F. et al. Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease. Arterioscler. Thromb. Vasc. Biol. 26, 2536–2540 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Dayal, S. & Lentz, S. R. ADMA and hyperhomocysteinemia. Vasc Med. 10 (Suppl. 1), 27–33 (2005).

    Article  Google Scholar 

  66. Stuhlinger, M. C. et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation 108, 933–938 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Zoccali, C. et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358, 2113–2117 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Matsumoto, Y. et al. Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease. J. Am. Soc. Nephrol. 18, 1525–1533 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Caplin, B. et al. Circulating methylarginine levels and the decline in renal function in patients with chronic kidney disease are modulated by DDAH1 polymorphisms. Kidney Int. 77, 459–467 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Gorenflo, M., Zheng, C., Werle, E., Fiehn, W. & Ulmer, H. E. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J. Cardiovasc. Pharmacol. 37, 489–492 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Pullamsetti, S. et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J. 19, 1175–1177 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Millatt, L. J. et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation 108, 1493–1498 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Sasaki, A., Doi, S., Mizutani, S. & Azuma, H. Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L1480–L1487 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Zakrzewicz, D. & Eickelberg, O. From arginine methylation to ADMA: a novel mechanism with therapeutic potential in chronic lung diseases. BMC Pulm. Med. 9, 5 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Savvidou, M. D. et al. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 361, 1511–1517 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Pettersson, A., Hedner, T. & Milsom, I. Increased circulating concentrations of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in pre-eclampsia. Acta Obstet. Gynecol. Scand. 77, 808–813 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Speer, P. D. et al. Elevated asymmetric dimethylarginine concentrations precede clinical pre-eclampsia, but not pregnancies with small-for-gestational-age infants. Am. J. Obstet. Gynecol. 198, e1–e7 (2008).

    Article  CAS  Google Scholar 

  78. Maas, R. et al. Plasma concentrations of asymmetric dimethylarginine (ADMA) in Colombian women with pre-eclampsia. JAMA 291, 823–824 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Kim, Y. J. et al. Reduced L-arginine level and decreased placental eNOS activity in preeclampsia. Placenta 27, 438–444 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Akbar, F. et al. Haplotypic association of DDAH1 with susceptibility to pre-eclampsia. Mol. Hum. Reprod. 11, 73–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Prefumo, F., Thilaganathan, B. & Whitley, G. S. First-trimester uterine artery resistance and maternal serum concentration of asymmetric dimethylarginine. Ultrasound Obstet. Gynecol. 31, 153–157 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Sydow, K., Mondon, C. E. & Cooke, J. P. Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA. Vasc. Med. 10 (Suppl. 1), 35–43 (2005).

    Article  Google Scholar 

  83. Sydow, K., Mondon, C. E., Schrader, J., Konishi, H. & Cooke, J. P. Dimethylarginine dimethylaminohydrolase overexpression enhances insulin sensitivity. Arterioscler. Thromb. Vasc. Biol. 28, 692–697 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lin, K. Y. et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106, 987–992 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Feil, R. & Kleppisch, T. NO/cGMP-dependent modulation of synaptic transmission. Handb. Exp. Pharmacol. 184, 529–560 (2008).

    Article  CAS  Google Scholar 

  86. Moncada, S. & Bolanos, J. P. Nitric oxide, cell bioenergetics and neurodegeneration. J. Neurobiol. 97, 1676–1689 (2006).

    CAS  Google Scholar 

  87. Ebadi, M. & Sharma, S. K. Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. Antioxid. Redox Signal. 5, 319–335 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Selley, M. L. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer's disease. Neurobiol. Aging 24, 903–907 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Abe, T., Tohgi, H., Murata, T., Isobe, C. & Sato, C. Reduction in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in the cerebrospinal fluid during aging and in patients with Alzheimer's disease. Neurosci. Lett. 312, 177–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Mulder, C. et al. Alzheimer's disease is not associated with altered concentrations of the nitric oxide synthase inhibitor asymmetric dimethylarginine in cerebrospinal fluid. J. Neural Transm. 109, 1203–1208 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Arlt, S. et al. Asymmetrical dimethylarginine is increased in plasma and decreased in cerebrospinal fluid of patients with Alzheimer's disease. Dement Geriatr. Cogn. Disord. 26, 58–64 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Garthwaite, J., Charles, S. L. & Chess-Williams, R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336, 385–388 (1988).

    Article  CAS  PubMed  Google Scholar 

  93. Sattler, R. et al. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284, 1845–1848 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Stanfa, L. C., Misra, C. & Dickenson, A. H. Amplification of spinal nociceptive transmission depends on the generation of nitric oxide in normal and carrageenan rats. Brain Res. 737, 92–98 (1996).

    Article  CAS  PubMed  Google Scholar 

  95. Meller, S. T., Cummings, C. P., Traub, R. J. & Gebhart, G. F. The role of nitric oxide in the development and maintenance of the hyperalgesia produced by intraplantar injection of carrageenan in the rat. Neuroscience 60, 367–374 (1994).

    Article  CAS  PubMed  Google Scholar 

  96. Thomsen, L. L. et al. Nitric oxide synthase activity in human breast cancer. Br. J. Cancer 72, 41–44 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cobbs, C. S., Brenman, J. E., Aldape, K. D., Bredt, D. S. & Israel, M. A. Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res. 55, 727–730 (1995).

    CAS  PubMed  Google Scholar 

  98. Tanriover, N. et al. Neuronal nitric oxide synthase expression in glial tumors: correlation with malignancy and tumor proliferation. Neurol. Res. 30, 940–944 (2008).

    Article  PubMed  Google Scholar 

  99. Ng, Q. S. et al. Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study. Lancet Oncol. 8, 111–118 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Tse, G. M. et al. Stromal nitric oxide synthase (NOS) expression correlates with the grade of mammary phyllodes tumour. J. Clin. Pathol. 58, 600–604 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nakamura, Y. et al. Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin. Cancer Res. 12, 1201–1207 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Nakamura, Y. et al. Nitric oxide in papillary thyroid carcinoma: induction of vascular endothelial growth factor D and correlation with lymph node metastasis. J. Clin. Endocrinol. Metab. 91, 1582–1585 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Kostourou, V., Robinson, S. P., Cartwright, J. E. & Whitley, G. S. Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis. Br. J. Cancer 87, 673–680 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kostourou, V., Robinson, S. P., Whitley, G. S. & Griffiths, J. R. Effects of overexpression of dimethylarginine dimethylaminohydrolase on tumor angiogenesis assessed by susceptibility magnetic resonance imaging. Cancer Res. 63, 4960–4966 (2003).

    CAS  PubMed  Google Scholar 

  105. Kostourou, V. et al. Overexpression of dimethylarginine dimethylaminohydrolase enhances tumor hypoxia: an insight into the relationship of hypoxia and angiogenesis in vivo. Neoplasia 6, 401–411 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tsikas, D. et al. Elevated plasma and urine levels of ADMA and 15(S)-8-iso-PGF2α in end-stage liver disease. Hepatology 38, 1063–1064 (2003).

    PubMed  Google Scholar 

  107. Nijveldt, R. J. et al. Elevation of asymmetric dimethylarginine (ADMA) in patients developing hepatic failure after major hepatectomy. J. Parenter. Enteral. Nutr. 28, 382–387 (2004).

    Article  CAS  Google Scholar 

  108. Richir, M. C. et al. The prominent role of the liver in the elimination of asymmetric dimethylarginine (ADMA) and the consequences of impaired hepatic function. J. Parenter. Enteral. Nutr. 32, 613–621 (2008).

    Article  CAS  Google Scholar 

  109. Hermenegildo, C. et al. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients. J. Clin. Endocrinol. Metab. 87, 5636–5640 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Arikan, E., Karadag, C. H. & Guldiken, S. Asymmetric dimethylarginine levels in thyroid diseases. J. Endocrinol. Invest. 30, 186–191 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Jones, L. C., Tran, C. T., Leiper, J. M., Hingorani, A. D. & Vallance, P. Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells. Biochem. Biophys. Res. Commun. 310, 836–843 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Bai, Y. et al. Common genetic variation in DDAH2 is associated with intracerebral hemorrhage in Chinese population: a multicenter case-control study in China. Clin. Sci. 117, 273–279 (2009).

    Article  CAS  Google Scholar 

  113. Ryan, R. et al. Gene polymorphism and requirement for vasopressor infusion after cardiac surgery. Ann. Thorac. Surg. 82, 895–901 (2006).

    Article  PubMed  Google Scholar 

  114. 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 

  115. Hu, X. et al. Vascular endothelial-specific dimethylarginine dimethylaminohydrolase-1-deficient mice reveal that vascular endothelium plays an important role in removing asymmetric dimethylarginine. Circulation 120, 2222–2229 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Dayoub, H. et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 108, 3042–3047 (2003). This study was the first to identify that endogenous NOS inhibitors were present at concentrations that are sufficient to cause tonic inhibition of NO synthesis and cardiovascular function in vivo.

    Article  CAS  PubMed  Google Scholar 

  117. Ueda, S. et al. Regulation of cytokine-induced nitric oxide synthesis by asymmetric dimethylarginine: role of dimethylarginine dimethylaminohydrolase. Circ. Res. 92, 226–233 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Ueda, S. et al. Involvement of asymmetric dimethylarginine (ADMA) in glomerular capillary loss and sclerosis in a rat model of chronic kidney disease (CKD). Life Sci. 84, 853–856 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Wadham, C. & Mangoni, A. A. Dimethylarginine dimethylaminohydrolase regulation: a novel therapeutic target in cardiovascular disease. Expert Opin. Drug Metab. Toxicol. 5, 303–319 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Achan, V. et al. all-trans-Retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ. Res. 90, 764–769 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Hu, T. et al. Farnesoid X receptor agonist reduces serum asymmetric dimethylarginine levels through hepatic dimethylarginine dimethylaminohydrolase-1 gene regulation. J. Biol. Chem. 281, 39831–39838 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Shibata, R. et al. Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischaemia in the early phase of diabetic nephropathy. Nephrol. Dial. Transplant 24, 1162–1629 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Tokuo, H. et al. Phosphorylation of neurofibromin by cAMP-dependent protein kinase is regulated via a cellular association of NG,NG-dimethylarginine dimethylaminohydrolase. FEBS Lett. 494, 48–53 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Leiper, J., Murray-Rust, J., McDonald, N. & Vallance, P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. Proc. Natl Acad. Sci. USA 99, 13527–13532 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Knipp, M., Braun, O., Gehrig, P. M., Sack, R. & Vasak, M. Zn(II)-free dimethylargininase-1 (DDAH-1) is inhibited upon specific Cys-S-nitrosylation. J. Biol. Chem. 278, 3410–3416 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Jiang, J. L. et al. Probucol decreases asymmetrical dimethylarginine level by alternation of protein arginine methyltransferase I and dimethylarginine dimethylaminohydrolase activity. Cardiovasc. Drugs Ther. 20, 281–294 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Tan, B. et al. Taurine protects against low-density lipoprotein-induced endothelial dysfunction by the DDAH/ADMA pathway. Vascul. Pharmacol. 46, 338–345 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Murray-Rust, J. et al. Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase. Nature Struct. Biol. 8, 679–683 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Frey, D., Braun, O., Briand, C., Vasak, M. & Grutter, M. G. Structure of the mammalian NOS regulator dimethylarginine dimethylaminohydrolase: a basis for the design of specific inhibitors. Structure 14, 901–911 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Vallance, P. et al. Inhibition of dimethylarginine dimethylaminohydrolase (DDAH) and arginine deiminase (ADI) by pentafluorophenyl (PFP) sulfonates. Chem. Commun. (Camb.) 2005, 5563–5565 (2005). This paper describes the identification of pentafluorophenyl sulphonates as potent inhibitors of DDAH activity. These compounds were the first non-substrate-based inhibitors of DDAH to be identified.

    Article  CAS  Google Scholar 

  131. Stuhlinger, M. C. et al. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 104, 2569–2575 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Rossiter, S. et al. Selective substrate-based inhibitors of mammalian dimethylarginine dimethylaminohydrolase. J. Med. Chem. 48, 4670–4678 (2005). This study describes a series of substrate-based inhibitors of DDAH that have significant selectivity for DDAH over NOS enzymes. This work demonstrates that these types of molecules are bioavailable in vivo and elevate circulating ADMA levels.

    Article  CAS  PubMed  Google Scholar 

  133. Knipp, M., Braun, O. & Vasak, M. Searching for DDAH inhibitors: S-nitroso-L-homocysteine is a chemical lead. J. Am. Chem. Soc. 127, 2372–2373 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Kotthaus, J., Schade, D., Muschick, N., Beitz, E. & Clement, B. Structure–activity relationship of novel and known inhibitors of human dimethylarginine dimethylaminohydrolase-1: alkenyl-amidines as new leads. Bioorg Med. Chem. 16, 10205–10209 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Lluis, M., Wang, Y., Monzingo, A. F., Fast, W. & Robertus, J. D. Characterization of C-alkyl amidines as bioavailable covalent reversible inhibitors of human DDAH-1. Chem. Med. Chem. 6, 81–88 (2011). This work describes the identification of alkyl amidines as covalent reversible inhibitors of DDAH and raises the possibility that stabilization of the covalent adduct may provide a strategy for the design of more potent DDAH inhibitors.

    Article  CAS  PubMed  Google Scholar 

  136. Wang, Y. et al. Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide. Biochemistry 48, 8624–8635 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Schade, D., Kotthaus, J. & Clement, B. Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease. Pharmacol. Ther. 126, 279–300 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Thiemermann, C. Nitric oxide and septic shock. Gen. Pharmacol. 29, 159–166 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Luo, Z. D. & Cizkova, D. The role of nitric oxide in nociception. Curr. Rev. Pain. 4, 459–466 (2000).

    Article  CAS  PubMed  Google Scholar 

  140. Van'T Hof, R. J. & Ralston, S. H. Nitric oxide and bone. Immunology 103, 255–261 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kubes, P. & McCafferty, D. M. Nitric oxide and intestinal inflammation. Am. J. Med. 109, 150–158 (2000).

    Article  CAS  PubMed  Google Scholar 

  142. Wada, K., Chatzipanteli, K., Kraydieh, S., Busto, R. & Dietrich, W. D. Inducible nitric oxide synthase expression after traumatic brain injury and neuroprotection with aminoguanidine treatment in rats. Neurosurgery 43, 1427–1536 (1998).

    CAS  PubMed  Google Scholar 

  143. Cooke, J. P. NO and angiogenesis. Atheroscler. Suppl. 4, 53–60 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Vallance, P. & Leiper, J. Blocking NO synthesis: how, where and why? Nature Rev. Drug Discov. 1, 939–950 (2002).

    Article  CAS  Google Scholar 

  145. Lopez, A. et al. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit. Care Med. 32, 21–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Hussein, Z. et al. Pharmacokinetics of the nitric oxide synthase inhibitor L-NG-methylarginine hydrochloride in patients with septic shock. Glaxo Wellcome International Septic Shock Study Group. Clin. Pharmacol. Ther. 65, 1–9 (1999).

    Article  CAS  PubMed  Google Scholar 

  147. Angus, D. C. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310 (2001).

    Article  CAS  PubMed  Google Scholar 

  148. Karlsson, S. et al. Incidence, treatment, and outcome of severe sepsis in ICU-treated adults in Finland: the Finnsepsis study. Intensive Care Med. 33, 435–43 (2007).

    Article  PubMed  Google Scholar 

  149. Blanco, J. et al. Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit. Care 12, R158 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Vincent, J. L. et al. Sepsis in European intensive care units: results of the SOAP study. Crit. Care Med. 34, 344–353 (2006).

    Article  PubMed  Google Scholar 

  151. Martin, G. S., Mannino, D. M., Eaton, S. & Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546–1554 (2003).

    Article  PubMed  Google Scholar 

  152. Dellinger, R. P. et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit. Care Med. 36, 296–327 (2008).

    Article  PubMed  Google Scholar 

  153. Levy, B. et al. Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside. Intensive Care Med. 36, 2019–2029 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Rees, D. D., Monkhouse, J. E., Cambridge, D. & Moncada, S. Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse. Br. J. Pharmacol. 124, 540–546 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Teale, D. M. & Atkinson, A. M. Inhibition of nitric oxide synthesis improves survival in a murine peritonitis model of sepsis that is not cured by antibiotics alone. J. Antimicrob. Chemother. 30, 839–8342 (1992).

    Article  CAS  PubMed  Google Scholar 

  156. Kilbourn, R. G. et al. Inhibition of interleukin-1-α-induced nitric oxide synthase in vascular smooth muscle and full reversal of interleukin-1-α-induced hypotension by Nω-amino-L-arginine. J. Natl Cancer Inst. 84, 1008–1016 (1992).

    Article  CAS  PubMed  Google Scholar 

  157. Nava, E., Palmer, R. M. & Moncada, S. The role of nitric oxide in endotoxic shock: effects of NG-monomethyl-L-arginine. J. Cardiovasc. Pharmacol. 20 (Suppl. 12), 132–134 (1992).

    Article  Google Scholar 

  158. Szabo, C., Southan, G. J. & Thiemermann, C. Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc. Natl Acad. Sci. USA 91, 12472–12476 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Liaudet, L. et al. Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, during rodent endotoxaemia. Clin. Sci. 90, 369–377 (1996).

    Article  CAS  Google Scholar 

  160. Liaudet, L. et al. Nonselective versus selective inhibition of inducible nitric oxide synthase in experimental endotoxic shock. J. Infect. Dis. 177, 127–132 (1998).

    Article  CAS  PubMed  Google Scholar 

  161. Su, F. et al. Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock. Shock 34, 243–249 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Schilling, J., Cakmakci, M., Battig, U. & Geroulanos, S. A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine, an inhibitor of the nitric oxide synthetase. Intensive Care Med. 19, 227–231 (1993).

    Article  CAS  PubMed  Google Scholar 

  163. Petros, A., Bennett, D. & Vallance, P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet 338, 1557–1558 (1991).

    Article  CAS  PubMed  Google Scholar 

  164. Petros, A. et al. Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc. Res. 28, 34–39 (1994).

    Article  CAS  PubMed  Google Scholar 

  165. Bakker, J. et al. Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit. Care Med. 32, 1–12 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Watson, D. et al. Cardiovascular effects of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002). Crit. Care Med. 32, 13–20 (2004).

    Article  CAS  PubMed  Google Scholar 

  167. McBride, A. E. & Silver, P. A. State of the arg: protein methylation at arginine comes of age. Cell 106, 5–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  168. Boisvert, F. M., Chenard, C. A. & Richard, S. Protein interfaces in signaling regulated by arginine methylation. Sci. STKE 2005, re2 (2005).

    PubMed  Google Scholar 

  169. Bedford, M. T. & Richard, S. Arginine methylation an emerging regulator of protein function. Mol. Cell 18, 263–272 (2005).

    Article  CAS  PubMed  Google Scholar 

  170. Brahms, H. et al. The C-terminal RG dipeptide repeats of the spliceosomal Sm proteins D1 and D3 contain symmetrical dimethylarginines, which form a major B-cell epitope for anti-Sm autoantibodies. J. Chem. Biol. 275, 17122–17129 (2000).

    Article  CAS  Google Scholar 

  171. Tang, J. et al. PRMT1 is the predominant type I protein arginine methyltransferase in mammalian cells. J. Biol. Chem. 275, 7723–7730 (2000).

    Article  CAS  PubMed  Google Scholar 

  172. Wang, Y. et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279–283 (2004).

    Article  CAS  PubMed  Google Scholar 

  173. Cuthbert, G. L. et al. Histone deimination antagonizes arginine methylation. Cell 118, 545–553 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Chang, B., Chen, Y., Zhao, Y. & Bruick, R. K. JMJD6 is a histone arginine demethylase. Science 318, 444–447 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Hong, J. R. et al. Phosphatidylserine receptor is required for the engulfment of dead apoptotic cells and for normal embryonic development in zebrafish. Development 131, 5417–5427 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Kunisaki, Y. et al. Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor. Blood 103, 3362–3364 (2004).

    Article  CAS  PubMed  Google Scholar 

  177. Zinellu, A. et al. Increased plasma asymmetric dimethylarginine (ADMA) levels in retinal venous occlusive disease. Clin. Biol. Lab. Med. 46, 387–392 (2008).

    CAS  Google Scholar 

  178. Wang, D. et al. Asymmetric dimethylarginine and lipid peroxidation products in early autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 51, 184–191 (2008).

    Article  CAS  PubMed  Google Scholar 

  179. Yilmaz, M. I. et al. ADMA levels correlate with proteinuria, secondary amyloidosis, and endothelial dysfunction. J. Am. Soc. Nephrol. 19, 388–395 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Lucke, T. et al. Elevated asymmetric dimethylarginine (ADMA) and inverse correlation between circulating ADMA and glomerular filtration rate in children with sporadic focal segmental glomerulosclerosis (FSGS). Nephrol. Dial. Transplant. 23, 734–740 (2008).

    Article  CAS  PubMed  Google Scholar 

  181. Altinova, A. E. et al. Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations. J. Clin. Endocrinol. Metab. 92, 1881–1885 (2007).

    Article  CAS  PubMed  Google Scholar 

  182. Kato, G. J. et al. Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death. Br. J. Haematol. 145, 506–513 (2009).

    Article  CAS  PubMed  Google Scholar 

  183. Schnog, J. B., Teerlink, T., van der Dijs, F. P., Duits, A. J. & Muskiet, F. A. Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease. Ann. Hematol. 84, 282–286 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Selley, M. L. Increased (E)-4-hydroxy-2-nonenal and asymmetric dimethylarginine concentrations and decreased nitric oxide concentrations in the plasma of patients with major depression. J. Affect. Disord. 80, 249–256 (2004).

    Article  CAS  PubMed  Google Scholar 

  185. Saitoh, M. et al. High plasma level of asymmetric dimethylarginine in patients with acutely exacerbated congestive heart failure: role in reduction of plasma nitric oxide level. Heart Vessels 18, 177–182 (2003).

    Article  PubMed  Google Scholar 

  186. Boger, R. H., Lentz, S. R., Bode-Boger, S. M., Knapp, H. R. & Haynes, W. G. Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin. Sci. 100, 161–167 (2001).

    Article  CAS  Google Scholar 

  187. Miyazaki, H. et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation 99, 1141–1146 (1999).

    Article  CAS  PubMed  Google Scholar 

  188. Yoo, J. H. & Lee, S. C. Elevated levels of plasma homocyst(e)ine and asymmetric dimethylarginine in elderly patients with stroke. Atherosclerosis 158, 425–430 (2001).

    Article  CAS  PubMed  Google Scholar 

  189. Matsuguma, K. et al. Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease. J. Am. Soc. Nephrol. 17, 2176–2183 (2006).

    Article  CAS  PubMed  Google Scholar 

  190. Tatematsu, S. et al. Role of nitric oxide-producing and -degrading pathways in coronary endothelial dysfunction in chronic kidney disease. J. Am. Soc. Nephrol. 18, 741–749 (2007).

    Article  CAS  PubMed  Google Scholar 

  191. Onozato, M. L. et al. Expression of NG,NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers. Diabetes 57, 172–180 (2008).

    Article  CAS  PubMed  Google Scholar 

  192. Ito, A. et al. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99, 3092–3095 (1999).

    Article  CAS  PubMed  Google Scholar 

  193. Weis, M. et al. Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis. Circulation 109, 500–505 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Yin, Q. F. & Xiong, Y. Pravastatin restores DDAH activity and endothelium-dependent relaxation of rat aorta after exposure to glycated protein. J. Cardiovasc. Pharmacol. 45, 525–532 (2005).

    Article  CAS  PubMed  Google Scholar 

  195. Yang, T. L. et al. Fenofibrate decreases asymmetric dimethylarginine level in cultured endothelial cells by inhibiting NF-κB activity. Naunyn Schmiedebergs Arch. Pharmacol. 371, 401–407 (2005).

    Article  CAS  PubMed  Google Scholar 

  196. Tang, W. J., Hu, C. P., Chen, M. F., Deng, P. Y. & Li, Y. J. Epigallocatechin gallate preserves endothelial function by reducing the endogenous nitric oxide synthase inhibitor level. Can. J. Physiol. Pharmacol. 84, 163–171 (2006).

    Article  CAS  PubMed  Google Scholar 

  197. Wakino, S. et al. Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats. Hypertens. Res. 28, 255–262 (2005).

    Article  CAS  PubMed  Google Scholar 

  198. Deng, S. et al. Aspirin protected against endothelial damage induced by LDL: role of endogenous NO synthase inhibitors in rats. Acta Pharmacol. Sin. 25, 1633–1639 (2004).

    CAS  PubMed  Google Scholar 

  199. Wang, Y., Zhang, M., Liu, Y. & Chen, M. The effect of nebivolol on asymmetric dimethylarginine system in spontaneously hypertension rats. Vascul. Pharmacol. 15 Dec 2010 (doi:10.1016/j.vph.2010.12.001).

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Acknowledgements

Research in the author's laboratories is funded by The Medical Research Council (J.L.), The Wellcome Trust (J.L.) and The British Heart Foundation (J.L. and M.N.).

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  1. MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, W12 0NN, London, UK

    James Leiper

  2. Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, Franklin Wilkins Building, 150 Stamford Street, SE1 9NH, London, UK

    Manasi Nandi

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University College London, UK, has filed patents relating to therapeutic inhibition of dimethylarginine dimethylaminohydrolase. James Leiper is an inventor on these patent applications. Manasi Nandi does not declare any competing financial interests.

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Glossary

K i

(Inhibitor dissociation constant).The Ki gives an indication of how potent an inhibitor is for a given target.

ORF

(Open reading frame). The sequence of a gene that contains the protein coding sequence.

IC50

The concentration of a compound that is required to achieve 50% inhibition of target activity.

Associative studies

Studies in which the levels of biomarkers or risk factors are associated with pathology.

5/6 subtotal nephrectomy

Removal of five-sixths of renal mass to model renal insufficiency in animal models.

eGFR

(Estimated glomerular filtration rate).The eGFR is used clinically to monitor renal function.

Pulmonary arterial pressure

Blood pressure in the pulmonary artery — the blood vessel that transports blood from the right ventricle to the lung — that is determined, in part, by the resistance of the pulmonary vasculature.

Right ventricular pressure

The blood pressure in the right ventricle of the heart. As the right ventricle supplies blood to the pulmonary circulation, right ventricular pressure reflects pulmonary vascular resistance.

Pre-eclampsia

Hypertension induced by pregnancy.

N-methyl-D-aspartate receptor

A glutamate receptor that is the predominant molecular device for controlling synaptic plasticity and memory function.

Tumour grade

The developmental stage of a cancerous tumour.

VEGF

(Vascular endothelial growth factor). A key signalling molecule that is responsible for the formation and function of blood vessels.

Neovascularization

The formation of functional, perfused microvascular networks.

Haploinsufficiency

Deletion of a single allele of any gene.

IL-1β

(Interleukin-1β). A key cytokine involved in inflammatory responses.

Response element

A sequence in the promoter of a gene that is bound by a transcription factor to modulate expression of the gene.

Redox inactivation

The inactivation of enzymes by changes in the redox state of a cell. Typically, enzymes that contain active-site residues that are sensitive to the redox state of the cell are inactivated by oxidative or nitrosative stress.

Tumour angiogenesis

The growth of new blood vessels into and around a growing tumour to maintain perfusion.

Fluid resuscitation

The medical practice of replenishing bodily fluid that is lost as a consequence of vascular leakage during sepsis.

Inotropic challenge

A dose of agent that increases the force of cardiac contraction

Vasopressor challenge

A dose of a vasoconstrictive agent that is administered with the intention of raising blood pressure.

Endotoxaemia

The presence of bacterial-derived endotoxins in the blood.

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Leiper, J., Nandi, M. The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov 10, 277–291 (2011). https://doi.org/10.1038/nrd3358

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