Review Article | Published:

Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy

Acta Pharmacologica Sinica (2018) | Download Citation



Diabetes mellitus is currently a major public health problem. A common complication of diabetes is cardiac dysfunction, which is recognized as a microvascular disease that leads to morbidity and mortality in diabetic patients. While ischemic events are commonly observed in diabetic patients, the risk for developing heart failure is also increased, independent of the severity of coronary artery disease and hypertension. This diabetes-associated clinical entity is considered a distinct disease process referred to as “diabetic cardiomyopathy”. However, it is not clear how diabetes promotes cardiac dysfunction. Vascular endothelial dysfunction is thought to be one of the key risk factors. The impact of diabetes on the endothelium involves several alterations, including hyperglycemia, fatty acid oxidation, reduced nitric oxide (NO), oxidative stress, inflammatory activation, and altered barrier function. The current review provides an update on mechanisms that specifically target endothelial dysfunction, which may lead to diabetic cardiomyopathy.

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  1. 1.

    Raev DC. Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type I diabetic patients. Diabetes Care. 1994;17:633–9.

  2. 2.

    Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34:29–34.

  3. 3.

    Echouffo-Tcheugui JB, Xu H, DeVore AD, Schulte PJ, Butler J, Yancy CW, et al. Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: findings from get with The Guidelines-Heart Failure registry. Am Heart J. 2016;182:9–20.

  4. 4.

    Shah AD, Langenberg C, Rapsomaniki E, Denaxas S, Pujades-Rodriguez M, Gale CP, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 2015;3:105–13.

  5. 5.

    Kho C, Lee A, Jeong D, Oh JG, Gorski PA, Fish K, et al. Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure. Nat Commun. 2015;6:7229.

  6. 6.

    Severson DL. Diabetic cardiomyopathy: recent evidence from mouse models of type 1 and type 2 diabetes. Can J Physiol Pharmacol. 2004;82:813–23.

  7. 7.

    Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972;30:595–602.

  8. 8.

    Schannwell CM, Schneppenheim M, Perings S, Plehn G, Strauer BE. Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy. Cardiology. 2002;98:33–39.

  9. 9.

    Leung M, Phan V, Whatmough M, Heritier S, Wong VW, Leung DY. Left ventricular diastolic reserve in patients with type 2 diabetes mellitus. Open Heart. 2015;2:e000214.

  10. 10.

    Patil VC, Patil HV, Shah KB, Vasani JD, Shetty P. Diastolic dysfunction in asymptomatic type 2 diabetes mellitus with normal systolic function. J Cardiovasc Dis Res. 2011;2:213–22.

  11. 11.

    Boyer JK, Thanigaraj S, Schechtman KB, Perez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol. 2004;93:870–5.

  12. 12.

    Walker AM, Patel PA, Rajwani A, Groves D, Denby C, Kearney L, et al. Diabetes mellitus is associated with adverse structural and functional cardiac remodelling in chronic heart failure with reduced ejection fraction. Diab Vasc Dis Res. 2016;13:331–40.

  13. 13.

    Henry RM, Paulus WJ, Kamp O, Kostense PJ, Spijkerman AM, Dekker JM, et al. Deteriorating glucose tolerance status is associated with left ventricular dysfunction—the Hoorn Study. Neth J Med. 2008;66:110–7.

  14. 14.

    Eguchi K, Boden-Albala B, Jin Z, Rundek T, Sacco RL, Homma S, et al. Association between diabetes mellitus and left ventricular hypertrophy in a multiethnic population. Am J Cardiol. 2008;101:1787–91.

  15. 15.

    Ilercil A, Devereux RB, Roman MJ, Paranicas M, O’Grady MJ, Welty TK, et al. Relationship of impaired glucose tolerance to left ventricular structure and function: The Strong Heart Study. Am Heart J. 2001;141:992–8.

  16. 16.

    Rerkpattanapipat P, D’Agostino RB Jr., Link KM, Shahar E, Lima JA, Bluemke DA, et al. Location of arterial stiffening differs in those with impaired fasting glucose versus diabetes: implications for left ventricular hypertrophy from the Multi-Ethnic Study of Atherosclerosis. Diabetes. 2009;58:946–53.

  17. 17.

    Shimizu M, Umeda K, Sugihara N, Yoshio H, Ino H, Takeda R, et al. Collagen remodelling in myocardia of patients with diabetes. J Clin Pathol. 1993;46:32–6.

  18. 18.

    Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, et al. Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest. 1977;60:884–99.

  19. 19.

    Yue Y, Meng K, Pu Y, Zhang X. Transforming growth factor beta (TGF-beta) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res Clin Pract. 2017;133:124–30.

  20. 20.

    Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014;57:660–71.

  21. 21.

    Ma¨kimattila S, Virkama¨ki A, Groop P-H, Cockcroft J, Utriainen T, Fagerudd J, et al. Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation. 1996;94:1276–82.

  22. 22.

    Ding Y, Vaziri ND, Coulson R, Kamanna VS, Roh DD. Effects of simulated hyperglycemia, insulin, and glucagon on endothelial nitric oxide synthase expression. Am J Physiol Endocrinol Metab. 2000;279:E11–7.

  23. 23.

    Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev. 2004;25:543–67.

  24. 24.

    Zurova-Nedelcevova J, Navarova J, Drabikova K, Jancinova V, Petrikova M, Bernatova I, et al. Participation of reactive oxygen species in diabetes-induced endothelial dysfunction. Neuro Endocrinol Lett. 2006;27(Suppl 2):168–71.

  25. 25.

    Sada K, Nishikawa T, Kukidome D, Yoshinaga T, Kajihara N, Sonoda K, et al. Hyperglycemia induces cellular hypoxia through production of mitochondrial ROS followed by suppression of aquaporin-1. PLoS One. 2016;11:e0158619.

  26. 26.

    Mandarino LJ, Finlayson J, Hassell JR. High glucose downregulates glucose transport activity in retinal capillary pericytes but not endothelial cells. Invest Ophthalmol Vis Sci. 1994;35:964–72.

  27. 27.

    Kaiser N, Sasson S, Feener EP, Boukobza-Vardi N, Higashi S, Moller DE, et al. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes. 1993;42:80–9.

  28. 28.

    Dobrina A, Rossi F. Metabolic properties of freshly isolated bovine endothelial cells. Biochim Biophys Acta. 1983;762:295–301.

  29. 29.

    Hansen SS, Aasum E, Hafstad AD. The role of NADPH oxidases in diabetic cardiomyopathy. Biochim Biophys Acta. 2017;1864(5 Pt B):1908–1913.

  30. 30.

    Helies-Toussaint C, Gambert S, Roller P, Tricot S, Lacour B, Grynberg A. Lipid metabolism in human endothelial cells. Biochim Et Biophys Acta-Mol Cell Biol Lipids. 2006;1761:765–74.

  31. 31.

    Patella F, Schug ZT, Persi E, Neilson LJ, Erami Z, Avanzato D, et al. Proteomics-based metabolic modeling reveals that fatty acid oxidation (FAO) controls endothelial cell (EC) permeability. Mol Cell Proteom. 2015;14:621–34.

  32. 32.

    Koziel A, Woyda-Ploszczyca A, Kicinska A, Jarmuszkiewicz W. The influence of high glucose on the aerobic metabolism of endothelial EA.hy926 cells. Pflug Arch. 2012;464:657–69.

  33. 33.

    Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature. 2015;520:192–97.

  34. 34.

    De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell. 2013;154:651–63.

  35. 35.

    Sone H, Deo BK, Kumagai AK. Enhancement of glucose transport by vascular endothelial growth factor in retinal endothelial cells. Invest Ophthalmol Vis Sci. 2000;41:1876–84.

  36. 36.

    Zhang Z, Apse K, Pang J, Stanton RC. High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells. J Biol Chem. 2000;275:40042–7.

  37. 37.

    Leopold JA, Cap A, Scribner AW, Stanton RC, Loscalzo J. Glucose-6-phosphate dehydrogenase deficiency promotes endothelial oxidant stress and decreases endothelial nitric oxide bioavailability. FASEB J. 2001;15:1771–3.

  38. 38.

    Leopold JA, Zhang YY, Scribner AW, Stanton RC, Loscalzo J. Glucose-6-phosphate dehydrogenase overexpression decreases endothelial cell oxidant stress and increases bioavailable nitric oxide. Arterioscler Thromb Vasc Biol. 2003;23:411–7.

  39. 39.

    Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest. 2001;108:1341–8.

  40. 40.

    Luo B, Soesanto Y, McClain DA. Protein modification by O-linked GlcNAc reduces angiogenesis by inhibiting Akt activity in endothelial cells. Arterioscler Thromb Vasc Biol. 2008;28:651–7.

  41. 41.

    Wautier JL, Zoukourian C, Chappey O, Wautier MP, Guillausseau PJ, Cao R, et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest. 1996;97:238–43.

  42. 42.

    Soro-Paavonen A, Zhang WZ, Venardos K, Coughlan MT, Harris E, Tong DC, et al. Advanced glycation end-products induce vascular dysfunction via resistance to nitric oxide and suppression of endothelial nitric oxide synthase. J Hypertens. 2010;28:780–8.

  43. 43.

    Esposito C, Fasoli G, Plati AR, Bellotti N, Conte MM, Cornacchia F, et al. Long-term exposure to high glucose up-regulates VCAM-induced endothelial cell adhesiveness to PBMC. Kidney Int. 2001;59:1842–9.

  44. 44.

    Katakami N. Mechanism of development of atherosclerosis and cardiovascular disease in diabetes mellitus. J Atheroscler Thromb. 2017;25:27–39.

  45. 45.

    Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes. 1997;46:1481–90.

  46. 46.

    Li J, Schmidt AM. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem. 1997;272:16498–506.

  47. 47.

    Dhar A, Dhar I, Desai KM, Wu L. Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose. Br J Pharmacol. 2010;161:1843–56.

  48. 48.

    Su Y, Qadri SM, Wu L, Liu L. Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells. Cardiovasc Diabetol. 2013;12:134.

  49. 49.

    Nielsen R, Norrelund H, Kampmann U, Botker HE, Moller N, Wiggers H. Effect of acute hyperglycemia on left ventricular contractile function in diabetic patients with and without heart failure: two randomized cross-over studies. PLoS One. 2013;8:e53247.

  50. 50.

    Viberti GC. Increased capillary permeability in diabetes mellitus and its relationship to microvascular angiopathy. Am J Med. 1983;75:81–4.

  51. 51.

    Hempel A, Maasch C, Heintze U, Lindschau C, Dietz R, Luft FC, et al. High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha. Circ Res. 1997;81:363–71.

  52. 52.

    Yuan SY, Ustinova EE, Wu MH, Tinsley JH, Xu W, Korompai FL, et al. Protein kinase C activation contributes to microvascular barrier dysfunction in the heart at early stages of diabetes. Circ Res. 2000;87:412–7.

  53. 53.

    Mellor H, Parker PJ. The extended protein kinase C superfamily. Biochem J. 1998;332(Pt 2):281–92.

  54. 54.

    Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science. 1996;272:728–31.

  55. 55.

    Haidari M, Zhang W, Willerson JT, Dixon RA. Disruption of endothelial adherens junctions by high glucose is mediated by protein kinase C-beta-dependent vascular endothelial cadherin tyrosine phosphorylation. Cardiovasc Diabetol. 2014;13:112.

  56. 56.

    Bauer HC, Traweger A, Zweimueller-Mayer J, Lehner C, Tempfer H, Krizbai I, et al. New aspects of the molecular constituents of tissue barriers. J Neural Transm (Vienna). 2011;118:7–21.

  57. 57.

    Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase c-beta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes. 2012;61:1573–83.

  58. 58.

    Chen S, Evans T, Mukherjee K, Karmazyn M, Chakrabarti S. Diabetes-induced myocardial structural changes: role of endothelin-1 and its receptors. J Mol Cell Cardiol. 2000;32:1621–9.

  59. 59.

    Liefeldt L, Rylski B, Walcher F, Manhart J, Kron S, Rosenke YW, et al. Effects of transgenic endothelin-2 overexpression on diabetic cardiomyopathy in rats. Eur J Clin Invest. 2010;40:203–10.

  60. 60.

    Muzaffar S, Shukla N, Bond M, Sala-Newby GB, Newby AC, Angelini GD, et al. Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate. Br J Pharmacol. 2008;155:847–56.

  61. 61.

    Muzaffar S, Jeremy JY, Angelini GD, Shukla N. NADPH oxidase 4 mediates upregulation of type 4 phosphodiesterases in human endothelial cells. J Cell Physiol. 2012;227:1941–50.

  62. 62.

    Csanyi G, Lepran I, Flesch T, Telegdy G, Szabo G, Mezei Z. Lack of endothelium-derived hyperpolarizing factor (EDHF) up-regulation in endothelial dysfunction in aorta in diabetic rats. Pharmacol Rep. 2007;59:447–55.

  63. 63.

    Sena CM, Pereira AM, Seica R. Endothelial dysfunction–a major mediator of diabetic vascular disease. Biochim Biophys Acta. 2013;1832:2216–31.

  64. 64.

    Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1996;27:567–74.

  65. 65.

    Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 1993;88:2510–6.

  66. 66.

    Heygate KM, Lawrence IG, Bennett MA, Thurston H. Impaired endothelium-dependent relaxation in isolated resistance arteries of spontaneously diabetic rats. Br J Pharmacol. 1995;116:3251–9.

  67. 67.

    Hamed S, Brenner B, Aharon A, Daoud D, Roguin A. Nitric oxide and superoxide dismutase modulate endothelial progenitor cell function in type 2 diabetes mellitus. Cardiovasc Diabetol. 2009;8:56.

  68. 68.

    El-Omar MM, Lord R, Draper NJ, Shah AM. Role of nitric oxide in posthypoxic contractile dysfunction of diabetic cardiomyopathy. Eur J Heart Fail. 2003;5:229–39.

  69. 69.

    Stockklauser-Farber K, Ballhausen T, Laufer A, Rosen P. Influence of diabetes on cardiac nitric oxide synthase expression and activity. Biochim Biophys Acta. 2000;1535:10–20.

  70. 70.

    Rosen P, Du X, Sui GZ. Molecular mechanisms of endothelial dysfunction in the diabetic heart. Adv Exp Med Biol. 2001;498:75–86.

  71. 71.

    Cho Y-E, Basu A, Dai A, Heldak M, Makino A. Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice. Am J Physiol Cell Physiol. 2013;305:1033.

  72. 72.

    Xia Z, Nagareddy PR, Guo Z, Zhang W, McNeill JH. Antioxidant N-acetylcysteine restores systemic nitric oxide availability and corrects depressions in arterial blood pressure and heart rate in diabetic rats. Free Radic Res. 2006;40:175–84.

  73. 73.

    Hattori Y, Kawasaki H, Abe K, Kanno M. Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol. 1991;261:H1086–94.

  74. 74.

    Voinea M, Georgescu A, Manea A, Dragomir E, Manduteanu I, Popov D, et al. Superoxide dismutase entrapped-liposomes restore the impaired endothelium-dependent relaxation of resistance arteries in experimental diabetes. Eur J Pharmacol. 2004;484:111–8.

  75. 75.

    Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease–a 30th anniversary update. Acta Physiol (Oxf). 2017;219:22–96.

  76. 76.

    Sukumar P, Viswambharan H, Imrie H, Cubbon RM, Yuldasheva N, Gage M, et al. Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction. Diabetes. 2013;62:2130–4.

  77. 77.

    Christ M, Bauersachs J, Liebetrau C, Heck M, Gunther A, Wehling M. Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes. 2002;51:2648–52.

  78. 78.

    Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, et al. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001;88:E14–22.

  79. 79.

    Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003;111:1201–9.

  80. 80.

    Alp NJ, Mussa S, Khoo J, Cai S, Guzik T, Jefferson A, et al. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J Clin Invest. 2003;112:725–35.

  81. 81.

    Schmidt K, Rehn M, Stessel H, Wolkart G, Mayer B. Evidence against tetrahydrobiopterin depletion of vascular tissue exposed to nitric oxide/superoxide or nitroglycerin. Free Radic Biol Med. 2010;48:145–52.

  82. 82.

    Kikuchi C, Kajikuri J, Hori E, Nagami C, Matsunaga T, Kimura K, et al. Aortic superoxide production at the early hyperglycemic stage in a rat type 2 diabetes model and the effects of pravastatin. Biol Pharm Bull. 2014;37:996–1002.

  83. 83.

    Pannirselvam M, Simon V, Verma S, Anderson T, Triggle CR. Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice. Br J Pharmacol. 2003;140:701–6.

  84. 84.

    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. 2000;43:1435–8.

  85. 85.

    Meininger CJ, Marinos RS, Hatakeyama K, Martinez-Zaguilan R, Rojas JD, Kelly KA, et al. Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency. Biochem J. 2000;349:353–6.

  86. 86.

    Zou M-H, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. 2002;109:817–26.

  87. 87.

    Abbasi F, Asagmi T, Cooke JP, Lamendola C, McLaughlin T, Reaven GM, et al. Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol. 2001;88:1201–3.

  88. 88.

    Xiong Y, Fu YF, Fu SH, Zhou HH. Elevated levels of the serum endogenous inhibitor of nitric oxide synthase and metabolic control in rats with streptozotocin-induced diabetes. J Cardiovasc Pharmacol. 2003;42:191–6.

  89. 89.

    Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, et al. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation. 2002;106:987–92.

  90. 90.

    Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991;87:432–8.

  91. 91.

    Patel H, Chen J, Das KC, Kavdia M. Hyperglycemia induces differential change in oxidative stress at gene expression and functional levels in HUVEC and HMVEC. Cardiovasc Diabetol. 2013;12:142.

  92. 92.

    Garcia Soriano F, Virag L, Jagtap P, Szabo E, Mabley JG, Liaudet L, et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med. 2001;7:108–13.

  93. 93.

    Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003;112:1049–57.

  94. 94.

    Chen S, Yang J, Xiang H, Chen W, Zhong H, Yang G, et al. Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction. Int J Mol Med. 2015;35:1103–8.

  95. 95.

    Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K, Yano M, et al. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes. 2006;55:120–7.

  96. 96.

    Wang XR, Zhang MW, Chen DD, Zhang Y, Chen AF. AMP-activated protein kinase rescues the angiogenic functions of endothelial progenitor cells via manganese superoxide dismutase induction in type 1 diabetes. Am J Physiol Endocrinol Metab. 2011;300:E1135–45.

  97. 97.

    Xie Z, Zhang J, Wu J, Viollet B, Zou MH. Upregulation of mitochondrial uncoupling protein-2 by the AMP-activated protein kinase in endothelial cells attenuates oxidative stress in diabetes. Diabetes. 2008;57:3222–30.

  98. 98.

    Mackenzie RM, Salt IP, Miller WH, Logan A, Ibrahim HA, Degasperi A, et al. Mitochondrial reactive oxygen species enhance AMP-activated protein kinase activation in the endothelium of patients with coronary artery disease and diabetes. Clin Sci (Lond). 2013;124:403–11.

  99. 99.

    Li FY, Lam KS, Tse HF, Chen C, Wang Y, Vanhoutte PM, et al. Endothelium-selective activation of AMP-activated protein kinase prevents diabetes mellitus-induced impairment in vascular function and reendothelialization via induction of heme oxygenase-1 in mice. Circulation. 2012;126:1267–77.

  100. 100.

    Viollet B, Lantier L, Devin-Leclerc J, Hebrard S, Amouyal C, Mounier R, et al. Targeting the AMPK pathway for the treatment of Type 2 diabetes. Front Biosci (Landmark Ed). 2009;14:3380–400.

  101. 101.

    Bereiter-Hahn J, Voth M. Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech. 1994;27:198–219.

  102. 102.

    Shenouda SM, Widlansky ME, Chen K, Xu G, Holbrook M, Tabit CE, et al. Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation. 2011;124:444–53.

  103. 103.

    Makino A, Scott BT, Dillmann WH. Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia. 2010;53:1783–94.

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The expert scientific advice of Dr. James K. Liao from the University of Chicago is gratefully acknowledged. This work was supported by a Scientist Development Grant (3SDG17270046) from AHA (to Rongxue Wu) and a Pilot and Feasibility grant at the Chicago DRTC (P30 DK020595) (to Rongxue Wu).

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  1. Department of Medicine, Section of Cardiology, University of Chicago, Chicago, USA

    • Maura Knapp
    • , Xin Tu
    •  & Rongxue Wu


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