Skip to main content Accessibility help

Reversibility of endothelial dysfunction in diabetes: role of polyphenols

  • N. Suganya (a1), E. Bhakkiyalakshmi (a1), D. V. L. Sarada (a1) and K. M. Ramkumar (a2)


The endothelium, a thin single sheet of endothelial cells, is a metabolically active layer that coats the inner surface of blood vessels and acts as an interface between the circulating blood and the vessel wall. The endothelium through the secretion of vasodilators and vasoconstrictors serves as a critical mediator of vascular homeostasis. During the development of the vascular system, it regulates cellular adhesion and vessel wall inflammation in addition to maintaining vasculogenesis and angiogenesis. A shift in the functions of the endothelium towards vasoconstriction, proinflammatory and prothrombic states characterise improper functioning of these cells, leading to endothelial dysfunction (ED), implicated in the pathogenesis of many diseases including diabetes. Major mechanisms of ED include the down-regulation of endothelial nitric oxide synthase levels, differential expression of vascular endothelial growth factor, endoplasmic reticulum stress, inflammatory pathways and oxidative stress. ED tends to be the initial event in macrovascular complications such as coronary artery disease, peripheral arterial disease, stroke and microvascular complications such as nephropathy, neuropathy and retinopathy. Numerous strategies have been developed to protect endothelial cells against various stimuli, of which the role of polyphenolic compounds in modulating the differentially regulated pathways and thus maintaining vascular homeostasis has been proven to be beneficial. This review addresses the factors stimulating ED in diabetes and the molecular mechanisms of natural polyphenol antioxidants in maintaining vascular homeostasis.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Reversibility of endothelial dysfunction in diabetes: role of polyphenols
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Reversibility of endothelial dysfunction in diabetes: role of polyphenols
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Reversibility of endothelial dysfunction in diabetes: role of polyphenols
      Available formats


Corresponding author

* Corresponding author: Dr K. M. Ramkumar, fax +91 44 2745 2343, email


Hide All
1. Galley, HF & Webster, NR (2004) Physiology of the endothelium. Br J Anaesth 93, 105113.
2. Cersosimo, E & DeFronzo, RA (2006) Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev 22, 423436.
3. Aird, WC (2007) Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100, 158173.
4. Rubanyi, GM (1991) Endothelium-derived relaxing and contracting factors. J Cell Biochem 46, 2736.
5. Shimokawa, H, Yasutake, H, Fujii, K, et al. (1996) The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol 28, 703711.
6. Rajendran, P, Rengarajan, T, Thangavel, J, et al. (2013) The vascular endothelium and human diseases. Int J Biol Sci 9, 10571069.
7. Chan, AK & Paredes, N (2013) The coagulation system in humans. Methods Mol Biol 992, 312.
8. Michiels, C (2003) Endothelial cell functions. J Cell Physiol 196, 430443.
9. Verhamme, P & Hoylaerts, MF (2006) The pivotal role of the endothelium in haemostasis and thrombosis. Acta Clin Belg 61, 213219.
10. Patan, S (2004) Vasculogenesis and angiogenesis. Cancer Treat Res 117, 332.
11. Zachary, I (2003) VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans 31, 11711177.
12. Olsson, AK, Dimberg, A, Kreuger, J, et al. (2006) VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol 7, 359371.
13. Biegelsen, ES & Loscalzo, J (1999) Endothelial function and atherosclerosis. Coron Artery Dis 10, 241256.
14. Carman, CV & Springer, TA (2004) A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 167, 377388.
15. Rahman, A, Anwar, KN & Malik, AB (2000) Protein kinase C-zeta mediates TNF-alpha-induced ICAM-1 gene transcription in endothelial cells. Am J Physiol Cell Physiol 279, C906C914.
16. Mestas, J & Ley, K (2008) Monocyte-endothelial cell interactions in the development of atherosclerosis. Trends Cardiovasc Med 18, 228232.
17. Gokce, N, Keaney, JF Jr, Hunter, LM, et al. (2002) Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation 105, 15671572.
18. Libby, P, Ridker, PM & Maseri, A (2002) Inflammation and atherosclerosis. Circulation 105, 11351143.
19. Wang, H, Wang, AX, Aylor, K, et al. (2013) Nitric oxide directly promotes vascular endothelial insulin transport. Diabetes 62, 40304042.
20. Joshua, IG, Zhang, Q, Falcone, JC, et al. (2005) Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: role of insulin and C-peptide. J Cell Biochem 96, 11491156.
21. Hamilton, SJ, Chew, GT & Watts, GF (2007) Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus. Diab Vasc Dis Res 4, 89102.
22. Addabbo, F, Montagnani, M & Goligorsky, MS (2009) Mitochondria and reactive oxygen species. Hypertension 53, 885892.
23. Basha, B, Samuel, SM, Triggle, CR, et al. (2012) Endothelial dysfunction in diabetes mellitus: possible involvement of endoplasmic reticulum stress? Exp Diabetes Res 2012, 481840.
24. De Vriese, AS, Verbeuren, TJ, Van de Voorde, J, et al. (2000) Endothelial dysfunction in diabetes. Br J Pharmacol 130, 963974.
25. Zanetti, M, Stocca, A, Dapas, B, et al. (2008) Inhibitory effects of fenofibrate on apoptosis and cell proliferation in human endothelial cells in high glucose. J Mol Med (Berl) 86, 185195.
26. Bucciarelli, LG, Pollreisz, A, Kebschull, M, et al. (2009) Inflammatory stress in primary venous and aortic endothelial cells of type 1 diabetic mice. Diab Vasc Dis Res 6, 249261.
27. Banumathi, E, Sheikpranbabu, S, Haribalaganesh, R, et al. (2010) PEDF prevents reactive oxygen species generation and retinal endothelial cell damage at high glucose levels. Exp Eye Res 90, 8996.
28. Wang, S, Peng, Q, Zhang, J, et al. (2008) Na+/H+exchanger is required for hyperglycaemia-induced endothelial dysfunction via calcium-dependent calpain. Cardiovasc Res 80, 255262.
29. Vanhoutte, PM, Shimokawa, H, Tang, EH, et al. (2009) Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196, 193222.
30. Kubota, T, Kubota, N, Kumagai, H, et al. (2011) Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab 13, 294307.
31. Kim, JA, Koh, KK & Quon, MJ (2005) The union of vascular and metabolic actions of insulin in sickness and in health. Arterioscler Thromb Vasc Biol 25, 889891.
32. Gogg, S, Smith, U & Jansson, PA (2009) Increased MAPK activation and impaired insulin signaling in subcutaneous microvascular endothelial cells in type 2 diabetes: the role of endothelin-1. Diabetes 58, 22382245.
33. Arcaro, G, Cretti, A, Balzano, S, et al. (2002) Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 105, 576582.
34. Muniyappa, R, Iantorno, M & Quon, MJ (2008) An integrated view of insulin resistance and endothelial dysfunction. Endocrinol Metab Clin North Am 37, 685711, ixx.
35. Cusi, K, Maezono, K, Osman, A, et al. (2000) Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 105, 311320.
36. Duerrschmidt, N, Wippich, N, Goettsch, W, et al. (2000) Endothelin-1 induces NAD(P)H oxidase in human endothelial cells. Biochem Biophys Res Commun 269, 713717.
37. Potenza, MA, Gagliardi, S, Nacci, C, et al. (2009) Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. Curr Med Chem 16, 94112.
38. Bakker, W, Eringa, EC, Sipkema, P, et al. (2009) Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell Tissue Res 335, 165189.
39. Erdei, N, Toth, A, Pasztor, ET, et al. (2006) High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion. Am J Physiol Heart Circ Physiol 291, H2107H2115.
40. Okon, EB, Chung, AW, Rauniyar, P, et al. (2005) Compromised arterial function in human type 2 diabetic patients. Diabetes 54, 24152423.
41. Okon, EB, Szado, T, Laher, I, et al. (2003) Augmented contractile response of vascular smooth muscle in a diabetic mouse model. J Vasc Res 40, 520530.
42. Bagi, Z, Koller, A & Kaley, G (2003) Superoxide-NO interaction decreases flow- and agonist-induced dilations of coronary arterioles in type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 285, H1404H1410.
43. Shin, HK, Kim, YK, Kim, KY, et al. (2004) Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of superoxide and cytokines via lectin-like oxidized low-density lipoprotein receptor-1 activation: prevention by cilostazol. Circulation 109, 10221028.
44. Lenaz, G, Bovina, C, D’Aurelio, M, et al. (2002) Role of mitochondria in oxidative stress and aging. Ann N Y Acad Sci 959, 199213.
45. Pangare, M & Makino, A (2012) Mitochondrial function in vascular endothelial cell in diabetes. J Smooth Muscle Res 48, 126.
46. Davidson, SM & Duchen, MR (2007) Endothelial mitochondria: contributing to vascular function and disease. Circ Res 100, 11281141.
47. Makino, A, Scott, BT & Dillmann, WH (2010) Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia 53, 17831794.
48. Griendling, KK & FitzGerald, GA (2003) Oxidative stress and cardiovascular injury: part II: animal and human studies. Circulation 108, 20342040.
49. Sugamura, K & Keaney, JF Jr (2011) Reactive oxygen species in cardiovascular disease. Free Radic Biol Med 51, 978992.
50. Paravicini, TM & Touyz, RM (2008) NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care 31, Suppl. 2, S170S180.
51. San Martin, A, Du, P, Dikalova, A, et al. (2007) Reactive oxygen species-selective regulation of aortic inflammatory gene expression in type 2 diabetes. Am J Physiol Heart Circ Physiol 292, H2073H2082.
52. Clemmer, JS, Xiang, L, Lu, S, et al. (2016) Hyperglycemia-mediated oxidative stress increases pulmonary vascular permeability. Microcirculation 23, 221229.
53. Matsumoto, S, Koshiishi, I, Inoguchi, T, et al. (2003) Confirmation of superoxide generation via xanthine oxidase in streptozotocin-induced diabetic mice. Free Radic Res 37, 767772.
54. Butler, R, Morris, AD, Belch, JJ, et al. (2000) Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35, 746751.
55. Inkster, ME, Cotter, MA & Cameron, NE (2007) Treatment with the xanthine oxidase inhibitor, allopurinol, improves nerve and vascular function in diabetic rats. Eur J Pharmacol 561, 6371.
56. Forstermann, U & Munzel, T (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113, 17081714.
57. Felaco, M, Grilli, A, De Lutiis, MA, et al. (2001) Endothelial nitric oxide synthase (eNOS) expression and localization in healthy and diabetic rat hearts. Ann Clin Lab Sci 31, 179186.
58. Taddei, S, Ghiadoni, L, Virdis, A, et al. (2003) Mechanisms of endothelial dysfunction: clinical significance and preventive non-pharmacological therapeutic strategies. Curr Pharm Des 9, 23852402.
59. Heitzer, T, Schlinzig, T, Krohn, K, et al. (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104, 26732678.
60. Heitzer, T, Krohn, K, Albers, S, et al. (2000) Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia 43, 14351438.
61. Francis, SH, Busch, JL, Corbin, JD, et al. (2010) cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 62, 525563.
62. Williams, IL, Wheatcroft, SB, Shah, AM, et al. (2002) Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans. Int J Obes Relat Metab Disord 26, 754764.
63. Shi, Y & Vanhoutte, PM (2009) Reactive oxygen-derived free radicals are key to the endothelial dysfunction of diabetes. J Diabetes 1, 151162.
64. Raman, CS, Li, H, Martasek, P, et al. (1998) Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Cell 95, 939950.
65. Hodnett, BL & Hester, RL (2007) Regulation of muscle blood flow in obesity. Microcirculation 14, 273288.
66. Hink, U, Li, H, Mollnau, H, et al. (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88, E14E22.
67. Lin, KY, Ito, A, Asagami, T, et al. (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106, 987992.
68. Munzel, T, Daiber, A, Ullrich, V, et al. (2005) Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol 25, 15511557.
69. Lajer, M, Tarnow, L, Jorsal, A, et al. (2008) Plasma concentration of asymmetric dimethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 31, 747752.
70. Krzyzanowska, K, Mittermayer, F, Wolzt, M, et al. (2007) Asymmetric dimethylarginine predicts cardiovascular events in patients with type 2 diabetes. Diabetes Care 30, 18341839.
71. Schulz, E, Jansen, T, Wenzel, P, et al. (2008) Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. Antioxid Redox Signal 10, 11151126.
72. Sheikh-Ali, M, Sultan, S, Alamir, AR, et al. (2010) Hyperglycemia-induced endoplasmic reticulum stress in endothelial cells. Nutrition 26, 11461150.
73. Nakagawa, T, Zhu, H, Morishima, N, et al. (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98103.
74. Nishitoh, H, Matsuzawa, A, Tobiume, K, et al. (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16, 13451355.
75. Ma, Y, Brewer, JW, Diehl, JA, et al. (2002) Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 318, 13511365.
76. Ozcan, U, Cao, Q, Yilmaz, E, et al. (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457461.
77. Beleznai, T & Bagi, Z (2012) Activation of hexosamine pathway impairs nitric oxide (NO)-dependent arteriolar dilations by increased protein O-GlcNAcylation. Vascul Pharmacol 56, 115121.
78. Luo, B, Soesanto, Y & McClain, DA (2008) Protein modification by O-linked GlcNAc reduces angiogenesis by inhibiting Akt activity in endothelial cells. Arterioscler Thromb Vasc Biol 28, 651657.
79. Scallan, JP, Hill, MA & Davis, MJ (2015) Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling. Cardiovasc Res 107, 8997.
80. Scherrer, U, Randin, D, Vollenweider, P, et al. (1994) Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest 94, 25112515.
81. Baron, AD, Steinberg, H, Brechtel, G, et al. (1994) Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Physiol 266, E248E253.
82. Laine, H, Sundell, J, Nuutila, P, et al. (2004) Insulin induced increase in coronary flow reserve is abolished by dexamethasone in young men with uncomplicated type 1 diabetes. Heart 90, 270276.
83. Iozzo, P, Chareonthaitawee, P, Rimoldi, O, et al. (2002) Mismatch between insulin-mediated glucose uptake and blood flow in the heart of patients with type II diabetes. Diabetologia 45, 14041409.
84. Lambadiari, V, Triantafyllou, K & Dimitriadis, GD (2015) Insulin action in muscle and adipose tissue in type 2 diabetes: the significance of blood flow. World J Diabetes 6, 626633.
85. Ardilouze, JL, Sotornik, R, Dennis, LA, et al. (2012) Failure to increase postprandial blood flow in subcutaneous adipose tissue is associated with tissue resistance to adrenergic stimulation. Diabetes Metab 38, 2733.
86. Langille, BL & Adamson, SL (1981) Relationship between blood flow direction and endothelial cell orientation at arterial branch sites in rabbits and mice. Circ Res 48, 481488.
87. Popov, D (2010) Endothelial cell dysfunction in hyperglycemia: phenotypic change, intracellular signaling modification, ultrastructural alteration, and potential clinical outcomes. Int J Diabetes Mellit 2, 189195.
88. Dokken, BB (2008) The pathophysiology of cardiovascular disease and diabetes: beyond blood pressure and lipids. Diabetes Spectr 21, 160165.
89. Simionescu, M (2007) Implications of early structural-functional changes in the endothelium for vascular disease. Arterioscler Thromb Vasc Biol 27, 266274.
90. Mather, KJ, Verma, S & Anderson, TJ (2001) Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 37, 13441350.
91. de Jager, J, Kooy, A, Schalkwijk, C, et al. (2014) Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. J Intern Med 275, 5970.
92. Pratley, RE & Gilbert, M (2008) Targeting incretins in type 2 diabetes: role of GLP-1 receptor agonists and DPP-4 inhibitors. Rev Diabet Stud 5, 7394.
93. Koska, J, Sands, M, Burciu, C, et al. (2015) Exenatide protects against glucose- and lipid-induced endothelial dysfunction: evidence for direct vasodilation effect of GLP-1 receptor agonists in humans. Diabetes 64, 26242635.
94. Torimoto, K, Okada, Y, Mori, H, et al. (2015) Effects of exenatide on postprandial vascular endothelial dysfunction in type 2 diabetes mellitus. Cardiovasc Diabetol 14, 25.
95. Thompson, CS (2013) Diabetic nephropathy: treatment with phosphodiesterase type 5 inhibitors. World J Diabetes 4, 124129.
96. Kuno, Y, Iyoda, M, Shibata, T, et al. (2011) Sildenafil, a phosphodiesterase type 5 inhibitor, attenuates diabetic nephropathy in non-insulin-dependent Otsuka Long-Evans Tokushima Fatty rats. Br J Pharmacol 162, 13891400.
97. Matsubara, J, Sugiyama, S, Sugamura, K, et al. (2012) A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J Am Coll Cardiol 59, 265276.
98. van Poppel, PC, Netea, MG, Smits, P, et al. (2011) Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care 34, 20722077.
99. Rieg, T, Masuda, T, Gerasimova, M, et al. (2014) Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol 306, F188F193.
100. Oelze, M, Kroller-Schon, S, Welschof, P, et al. (2014) The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLOS ONE 9, e112394.
101. Han, Y, Cho, YE, Ayon, R, et al. (2015) SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery. Am J Physiol Lung Cell Mol Physiol 309, L1027L1036.
102. Wenzel, P, Oelze, M, Coldewey, M, et al. (2007) Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates. Arterioscler Thromb Vasc Biol 27, 17291735.
103. Schuhmacher, S, Oelze, M, Bollmann, F, et al. (2011) Vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetranitrate but not isosorbide-5-mononitrate therapy. Diabetes 60, 26082616.
104. Hambrecht, R, Wolf, A, Gielen, S, et al. (2000) Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 342, 454460.
105. Fuchsjager-Mayrl, G, Pleiner, J, Wiesinger, GF, et al. (2002) Exercise training improves vascular endothelial function in patients with type 1 diabetes. Diabetes Care 25, 17951801.
106. Colberg, SR, Sigal, RJ, Fernhall, B, et al. (2010) Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement executive summary. Diabetes Care 33, 26922696.
107. Boule, NG, Haddad, E, Kenny, GP, et al. (2001) Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA 286, 12181227.
108. Lee, S, Park, Y & Zhang, C (2011) Exercise training prevents coronary endothelial dysfunction in type 2 diabetic mice. Am J Biomed Sci 3, 241252.
109. May, JM & Qu, ZC (2011) Ascorbic acid prevents oxidant-induced increases in endothelial permeability. Biofactors 37, 4650.
110. Ceriello, A, Piconi, L, Esposito, K, et al. (2007) Telmisartan shows an equivalent effect of vitamin C in further improving endothelial dysfunction after glycemia normalization in type 1 diabetes. Diabetes Care 30, 16941698.
111. Hoffman, RP, Dye, AS & Bauer, JA (2012) Ascorbic acid blocks hyperglycemic impairment of endothelial function in adolescents with type 1 diabetes. Pediatr Diabetes 13, 607610.
112. Mason, SA, Della Gatta, PA, Snow, RJ, et al. (2016) Ascorbic acid supplementation improves skeletal muscle oxidative stress and insulin sensitivity in people with type 2 diabetes: findings of a randomized controlled study. Free Radic Biol Med 93, 227238.
113. Wotherspoon, F, Laight, DW, Turner, C, et al. (2008) The effect of oral folic acid upon plasma homocysteine, endothelial function and oxidative stress in patients with type 1 diabetes and microalbuminuria. Int J Clin Pract 62, 569574.
114. Sudchada, P, Saokaew, S, Sridetch, S, et al. (2012) Effect of folic acid supplementation on plasma total homocysteine levels and glycemic control in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract 98, 151158.
115. Wiltshire, EJ, Gent, R, Hirte, C, et al. (2002) Endothelial dysfunction relates to folate status in children and adolescents with type 1 diabetes. Diabetes 51, 22822286.
116. Schneider, MP, Schneider, A, Jumar, A, et al. (2014) Effects of folic acid on renal endothelial function in patients with diabetic nephropathy: results from a randomized trial. Clin Sci (Lond) 127, 499505.
117. Ebbing, M, Bonaa, KH, Nygard, O, et al. (2009) Cancer incidence and mortality after treatment with folic acid and vitamin B12 . JAMA 302, 21192126.
118. Yiu, YF, Yiu, KH, Siu, CW, et al. (2013) Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes. Atherosclerosis 227, 140146.
119. Alyami, A, Soares, MJ, Sherriff, JL, et al. (2014) Vitamin D & endothelial function. Indian J Med Res 140, 483490.
120. Riek, AE, Oh, J, Sprague, JE, et al. (2012) Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients. J Biol Chem 287, 3848238494.
121. Dhein, S, Kabat, A, Olbrich, A, et al. (2003) Effect of chronic treatment with vitamin E on endothelial dysfunction in a type I in vivo diabetes mellitus model and in vitro . J Pharmacol Exp Ther 305, 114122.
122. Skyrme-Jones, RA, O’Brien, RC, Berry, KL, et al. (2000) Vitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled study. J Am Coll Cardiol 36, 94102.
123. Economides, PA, Khaodhiar, L, Caselli, A, et al. (2005) The effect of vitamin E on endothelial function of micro- and macrocirculation and left ventricular function in type 1 and type 2 diabetic patients. Diabetes 54, 204211.
124. Habauzit, V & Morand, C (2012) Evidence for a protective effect of polyphenols-containing foods on cardiovascular health: an update for clinicians. Ther Adv Chronic Dis 3, 87106.
125. Hoffman, RP (2014) Vascular endothelial dysfunction and nutritional compounds in early type 1 diabetes. Curr Diabetes Rev 10, 201207.
126. Gorinstein, S, Caspi, A, Libman, I, et al. (2006) Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. J Agric Food Chem 54, 18871892.
127. Geleijnse, JM, Launer, LJ, Van der Kuip, DA, et al. (2002) Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study. Am J Clin Nutr 75, 880886.
128. Manach, C, Williamson, G, Morand, C, et al. (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81, 230S242S.
129. Kroon, PA, Clifford, MN, Crozier, A, et al. (2004) How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr 80, 1521.
130. Mooradian, AD & Haas, MJ (2011) Glucose-induced endoplasmic reticulum stress is independent of oxidative stress: a mechanistic explanation for the failure of antioxidant therapy in diabetes. Free Radic Biol Med 50, 11401143.
131. Alderton, WK, Cooper, CE & Knowles, RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357, 593615.
132. Mount, PF, Kemp, BE & Power, DA (2007) Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol 42, 271279.
133. Barbosa, VA, Luciano, TF, Marques, SO, et al. (2013) Acute exercise induce endothelial nitric oxide synthase phosphorylation via Akt and AMP-activated protein kinase in aorta of rats: role of reactive oxygen species. Int J Cardiol 167, 29832988.
134. Muniyappa, R, Montagnani, M, Koh, KK, et al. (2007) Cardiovascular actions of insulin. Endocr Rev 28, 463491.
135. Federici, M, Pandolfi, A, De Filippis, EA, et al. (2004) G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation 109, 399405.
136. Jiang, ZY, Lin, YW, Clemont, A, et al. (1999) Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 104, 447457.
137. Asaba, K, Tojo, A, Onozato, ML, et al. (2005) Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int 67, 18901898.
138. Beckman, JS & Koppenol, WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271, C1424C1437.
139. Liu, Z, Jiang, C, Zhang, J, et al. (2015) Resveratrol inhibits inflammation and ameliorates insulin resistant endothelial dysfunction via regulation of AMP-activated protein kinase and sirtuin 1 activities. J Diabetes 8, 324335.
140. Arrick, DM, Sun, H, Patel, KP, et al. (2011) Chronic resveratrol treatment restores vascular responsiveness of cerebral arterioles in type 1 diabetic rats. Am J Physiol Heart Circ Physiol 301, H696H703.
141. Machha, A, Achike, FI, Mustafa, AM, et al. (2007) Quercetin, a flavonoid antioxidant, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas. Nitric Oxide 16, 442447.
142. Zhao, LR, Du, YJ, Chen, L, et al. (2014) Quercetin protects against high glucose-induced damage in bone marrow-derived endothelial progenitor cells. Int J Mol Med 34, 10251031.
143. Li, PG, Sun, L, Han, X, et al. (2012) Quercetin induces rapid eNOS phosphorylation and vasodilation by an Akt-independent and PKA-dependent mechanism. Pharmacology 89, 220228.
144. Tian, S, Tang, J, Liu, H, et al. (2012) Propyl gallate plays a nephroprotective role in early stage of diabetic nephropathy associated with suppression of glomerular endothelial cell proliferation and angiogenesis. Exp Diabetes Res 2012, 209567.
145. Tian, S, Gan, Y, Li, J, et al. (2011) Imbalance of glomerular VEGF–NO axis in diabetic rats: prevention by chronic therapy with propyl gallate. J Nephrol 24, 499506.
146. Roghani, M, Vaez Mahdavi, MR, Jalali-Nadoushan, MR, et al. (2013) Chronic administration of daidzein, a soybean isoflavone, improves endothelial dysfunction and attenuates oxidative stress in streptozotocin-induced diabetic rats. Phytother Res 27, 112117.
147. Yin, Y, Qi, F, Song, Z, et al. (2014) Ferulic acid combined with astragaloside IV protects against vascular endothelial dysfunction in diabetic rats. Biosci Trends 8, 217226.
148. Rizza, S, Muniyappa, R, Iantorno, M, et al. (2011) Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab 96, E782E792.
149. Jang, HJ, Ridgeway, SD & Kim, JA (2013) Effects of the green tea polyphenol epigallocatechin-3-gallate on high-fat diet-induced insulin resistance and endothelial dysfunction. Am J Physiol Endocrinol Metab 305, E1444E1451.
150. Zhang, W, Li, R, Li, J, et al. (2013) Alpha-linolenic acid exerts an endothelial protective effect against high glucose injury via PI3K/Akt pathway. PLOS ONE 8, e68489.
151. Bhardwaj, P, Khanna, D & Balakumar, P (2014) Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities. Cardiovasc Toxicol 14, 4151.
152. Tang, WJ, Hu, CP, Chen, MF, et al. (2006) Epigallocatechin gallate preserves endothelial function by reducing the endogenous nitric oxide synthase inhibitor level. Can J Physiol Pharmacol 84, 163171.
153. Li Volti, G, Salomone, S, Sorrenti, V, et al. (2011) Effect of silibinin on endothelial dysfunction and ADMA levels in obese diabetic mice. Cardiovasc Diabetol 10, 62.
154. Zhang, M, Wang, CM, Li, J, et al. (2013) Berberine protects against palmitate-induced endothelial dysfunction: involvements of upregulation of AMPK and eNOS and downregulation of NOX4. Mediators Inflamm 2013, 260464.
155. Wang, Y, Huang, Y, Lam, KS, et al. (2009) Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res 82, 484492.
156. Ferrara, N (2001) Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280, C1358C1366.
157. Wirostko, B, Wong, TY & Simo, R (2008) Vascular endothelial growth factor and diabetic complications. Prog Retin Eye Res 27, 608621.
158. Simo, R & Hernandez, C (2008) Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy. Diabetologia 51, 15741580.
159. Schrijvers, BF, Flyvbjerg, A & De Vriese, AS (2004) The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int 65, 20032017.
160. Nakagawa, T, Kosugi, T, Haneda, M, et al. (2009) Abnormal angiogenesis in diabetic nephropathy. Diabetes 58, 14711478.
161. Yoon, YS, Uchida, S, Masuo, O, et al. (2005) Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation 111, 20732085.
162. Verheyen, A, Peeraer, E, Lambrechts, D, et al. (2013) Therapeutic potential of VEGF and VEGF-derived peptide in peripheral neuropathies. Neuroscience 244, 7789.
163. Verheul, HM & Pinedo, HM (2007) Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7, 475485.
164. Mrudula, T, Suryanarayana, P, Srinivas, PN, et al. (2007) Effect of curcumin on hyperglycemia-induced vascular endothelial growth factor expression in streptozotocin-induced diabetic rat retina. Biochem Biophys Res Commun 361, 528532.
165. Kowluru, RA & Kanwar, M (2007) Effects of curcumin on retinal oxidative stress and inflammation in diabetes. Nutr Metab (Lond) 4, 8.
166. Sawatpanich, T, Petpiboolthai, H, Punyarachun, B, et al. (2010) Effect of curcumin on vascular endothelial growth factor expression in diabetic mice kidney induced by streptozotocin. J Med Assoc Thai 93, Suppl. 2, S1S8.
167. Shin, JY, Sohn, J & Park, KH (2013) Chlorogenic acid decreases retinal vascular hyperpermeability in diabetic rat model. J Korean Med Sci 28, 608613.
168. Wang, Y, Pampou, S, Fujikawa, K, et al. (2004) Opposing effect of angiopoietin-1 on VEGF-mediated disruption of endothelial cell-cell interactions requires activation of PKC beta. J Cell Physiol 198, 5361.
169. Premanand, C, Rema, M, Sameer, MZ, et al. (2006) Effect of curcumin on proliferation of human retinal endothelial cells under in vitro conditions. Invest Ophthalmol Vis Sci 47, 21792184.
170. Chen, J, Dai, M & Wang, Y (2014) Paeonol inhibits proliferation of vascular smooth muscle cells stimulated by high glucose via Ras-Raf-ERK1/2 signaling pathway in coculture model. Evid Based Complement Alternat Med 2014, 484269.
171. Gao, R, Zhu, BH, Tang, SB, et al. (2008) Scutellarein inhibits hypoxia- and moderately-high glucose-induced proliferation and VEGF expression in human retinal endothelial cells. Acta Pharmacol Sin 29, 707712.
172. Tian, C, Zhang, R, Ye, X, et al. (2013) Resveratrol ameliorates high-glucose-induced hyperpermeability mediated by caveolae via VEGF/KDR pathway. Genes Nutr 8, 231239.
173. Artwohl, M, Muth, K, Kosulin, K, et al. (2007) R-(+)-alpha-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1. Am J Physiol Endocrinol Metab 293, E681E689.
174. Simons, M (2005) Angiogenesis, arteriogenesis, and diabetes: paradigm reassessed? J Am Coll Cardiol 46, 835837.
175. Lerman, OZ, Galiano, RD, Armour, M, et al. (2003) Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia. Am J Pathol 162, 303312.
176. Naruse, K, Rask-Madsen, C, Takahara, N, et al. (2006) Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance. Diabetes 55, 691698.
177. Park, CW, Kim, HW, Lim, JH, et al. (2009) Vascular endothelial growth factor inhibition by dRK6 causes endothelial apoptosis, fibrosis, and inflammation in the heart via the Akt/eNOS axis in db/db mice. Diabetes 58, 26662676.
178. Nakamura, N, Naruse, K, Kobayashi, Y, et al. (2011) High glucose impairs the proliferation and increases the apoptosis of endothelial progenitor cells by suppression of Akt. J Diabetes Investig 2, 262270.
179. Tufro, A & Veron, D (2012) VEGF and podocytes in diabetic nephropathy. Semin Nephrol 32, 385393.
180. Yang, Z, Mo, X, Gong, Q, et al. (2008) Critical effect of VEGF in the process of endothelial cell apoptosis induced by high glucose. Apoptosis 13, 13311343.
181. Yang, KS, Lim, JH, Kim, TW, et al. (2014) Vascular endothelial growth factor-receptor 1 inhibition aggravates diabetic nephropathy through eNOS signaling pathway in db/db mice. PLOS ONE 9, e94540.
182. Nakagawa, T, Sato, W, Kosugi, T, et al. (2013) Uncoupling of VEGF with endothelial NO as a potential mechanism for abnormal angiogenesis in the diabetic nephropathy. J Diabetes Res 2013, 184539.
183. Benyair, R, Ron, E & Lederkremer, GZ (2011) Protein quality control, retention, and degradation at the endoplasmic reticulum. Int Rev Cell Mol Biol 292, 197280.
184. Luo, D, He, Y, Zhang, H, et al. (2008) AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response. J Biol Chem 283, 1190511912.
185. Gharavi, NM, Gargalovic, PS, Chang, I, et al. (2007) High-density lipoprotein modulates oxidized phospholipid signaling in human endothelial cells from proinflammatory to anti-inflammatory. Arterioscler Thromb Vasc Biol 27, 13461353.
186. Friedlander, R, Jarosch, E, Urban, J, et al. (2000) A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat Cell Biol 2, 379384.
187. Parmar, VM & Schroder, M (2012) Sensing endoplasmic reticulum stress. Adv Exp Med Biol 738, 153168.
188. Yoneda, T, Imaizumi, K, Oono, K, et al. (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276, 1393513940.
189. Xu, C, Bailly-Maitre, B & Reed, JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115, 26562664.
190. McCullough, KD, Martindale, JL, Klotz, LO, et al. (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21, 12491259.
191. Chen, Y, Wang, JJ, Li, J, et al. (2012) Activating transcription factor 4 mediates hyperglycaemia-induced endothelial inflammation and retinal vascular leakage through activation of STAT3 in a mouse model of type 1 diabetes. Diabetologia 55, 25332545.
192. Tsiotra, PC & Tsigos, C (2006) Stress, the endoplasmic reticulum, and insulin resistance. Ann N Y Acad Sci 1083, 6376.
193. Zhang, X, Fu, Y, Xu, X, et al. (2014) PERK pathway are involved in NO-induced apoptosis in endothelial cells cocultured with RPE under high glucose conditions. Nitric Oxide 40, 1016.
194. Kaufman, RJ (2002) Orchestrating the unfolded protein response in health and disease. J Clin Invest 110, 13891398.
195. Li, J, Wang, JJ, Yu, Q, et al. (2009) Endoplasmic reticulum stress is implicated in retinal inflammation and diabetic retinopathy. FEBS Lett 583, 15211527.
196. Salminen, A, Kauppinen, A, Hyttinen, JM, et al. (2010) Endoplasmic reticulum stress in age-related macular degeneration: trigger for neovascularization. Mol Med 16, 535542.
197. Wang, S, Park, JK & Duh, EJ (2012) Novel targets against retinal angiogenesis in diabetic retinopathy. Curr Diab Rep 12, 355363.
198. Sheikh-Ali, M, Sultan, S, Alamir, AR, et al. (2010) Effects of antioxidants on glucose-induced oxidative stress and endoplasmic reticulum stress in endothelial cells. Diabetes Res Clin Pract 87, 161166.
199. Song, J, Li, J, Hou, F, et al. (2015) Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells. Metabolism 64, 428437.
200. Guo, H, Callaway, JB & Ting, JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21, 677687.
201. Takeuchi, O & Akira, S (2010) Pattern recognition receptors and inflammation. Cell 140, 805820.
202. Mohamed, IN, Hafez, SS, Fairaq, A, et al. (2014) Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet. Diabetologia 57, 413423.
203. Wu, J, Xu, X, Li, Y, et al. (2014) Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol 745, 5968.
204. Li, Y, Yang, J, Chen, MH, et al. (2015) Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner. Pharmacol Res 99, 101115.
205. Zhao, Y, Li, Q, Zhao, W, et al. (2015) Astragaloside IV and cycloastragenol are equally effective in inhibition of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in the endothelium. J Ethnopharmacol 169, 210218.
206. Natsume, Y, Ito, S, Satsu, H, et al. (2009) Protective effect of quercetin on ER stress caused by calcium dynamics dysregulation in intestinal epithelial cells. Toxicology 258, 164175.
207. Reiling, JH, Clish, CB, Carette, JE, et al. (2011) A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin. Proc Natl Acad Sci U S A 108, 1175611765.
208. Szegezdi, E, Logue, SE, Gorman, AM, et al. (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7, 880885.
209. Suganya, N, Bhakkiyalakshmi, E, Suriyanarayanan, S, et al. (2014) Quercetin ameliorates tunicamycin-induced endoplasmic reticulum stress in endothelial cells. Cell Prolif 47, 231240.
210. Cuzzocrea, S (2005) Shock, inflammation and PARP. Pharmacol Res 52, 7282.
211. Buluc, M & Demirel-Yilmaz, E (2006) Resveratrol decreases calcium sensitivity of vascular smooth muscle and enhances cytosolic calcium increase in endothelium. Vascul Pharmacol 44, 231237.
212. Li, C, Wang, L, Huang, K, et al. (2012) Endoplasmic reticulum stress in retinal vascular degeneration: protective role of resveratrol. Invest Ophthalmol Vis Sci 53, 32413249.
213. Du, XL, Edelstein, D, Rossetti, L, et al. (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 97, 1222212226.
214. Durier, S, Fassot, C, Laurent, S, et al. (2003) Physiological genomics of human arteries: quantitative relationship between gene expression and arterial stiffness. Circulation 108, 18451851.
215. Gao, L & Mann, GE (2009) Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. Cardiovasc Res 82, 920.
216. Amiri, F, Virdis, A, Neves, MF, et al. (2004) Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation 110, 22332240.
217. Rahman, A & Fazal, F (2011) Blocking NF-kappaB: an inflammatory issue. Proc Am Thorac Soc 8, 497503.
218. Viatour, P, Merville, MP, Bours, V, et al. (2005) Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci 30, 4352.
219. Xiao, L, Liu, Y & Wang, N (2014) New paradigms in inflammatory signaling in vascular endothelial cells. Am J Physiol Heart Circ Physiol 306, H317H325.
220. Takaishi, H, Taniguchi, T, Takahashi, A, et al. (2003) High glucose accelerates MCP-1 production via p38 MAPK in vascular endothelial cells. Biochem Biophys Res Commun 305, 122128.
221. Natali, A, Toschi, E, Baldeweg, S, et al. (2006) Clustering of insulin resistance with vascular dysfunction and low-grade inflammation in type 2 diabetes. Diabetes 55, 11331140.
222. Zhang, H, Dellsperger, KC & Zhang, C (2012) The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update. Basic Res Cardiol 107, 237.
223. Csiszar, A, Smith, K, Labinskyy, N, et al. (2006) Resveratrol attenuates TNF-alpha-induced activation of coronary arterial endothelial cells: role of NF-kappaB inhibition. Am J Physiol Heart Circ Physiol 291, H1694H1699.
224. Dayoub, O, Andriantsitohaina, R & Clere, N (2013) Pleiotropic beneficial effects of epigallocatechin gallate, quercetin and delphinidin on cardiovascular diseases associated with endothelial dysfunction. Cardiovasc Hematol Agents Med Chem 11, 249264.
225. Wongeakin, N, Bhattarakosol, P & Patumraj, S (2014) Molecular mechanisms of curcumin on diabetes-induced endothelial dysfunctions: Txnip, ICAM-1, and NOX2 expressions. Biomed Res Int 2014, 161346.
226. Gupta, SK, Kumar, B, Nag, TC, et al. (2011) Curcumin prevents experimental diabetic retinopathy in rats through its hypoglycemic, antioxidant, and anti-inflammatory mechanisms. J Ocul Pharmacol Ther 27, 123130.
227. Rungseesantivanon, S, Thenchaisri, N, Ruangvejvorachai, P, et al. (2010) Curcumin supplementation could improve diabetes-induced endothelial dysfunction associated with decreased vascular superoxide production and PKC inhibition. BMC Complement Altern Med 10, 57.
228. Mahmoud, MF, Hassan, NA, El Bassossy, HM, et al. (2013) Quercetin protects against diabetes-induced exaggerated vasoconstriction in rats: effect on low grade inflammation. PLOS ONE 8, e63784.
229. Yamagata, K, Miyashita, A, Matsufuji, H, et al. (2010) Dietary flavonoid apigenin inhibits high glucose and tumor necrosis factor alpha-induced adhesion molecule expression in human endothelial cells. J Nutr Biochem 21, 116124.
230. Tuttle, KR & Anderson, PW (2003) A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta inhibition. Am J Kidney Dis 42, 456465.
231. Yang, J, Han, Y, Chen, C, et al. (2013) EGCG attenuates high glucose-induced endothelial cell inflammation by suppression of PKC and NF-kappaB signaling in human umbilical vein endothelial cells. Life Sci 92, 589597.
232. Kim, SW, Kim, CE & Kim, MH (2011) Flavonoids inhibit high glucose-induced up-regulation of ICAM-1 via the p38 MAPK pathway in human vein endothelial cells. Biochem Biophys Res Commun 415, 602607.
233. Gao, Y, Zhang, J, Li, G, et al. (2015) Protection of vascular endothelial cells from high glucose-induced cytotoxicity by emodin. Biochem Pharmacol 94, 3945.
234. Jayakumar, T, Chang, CC, Lin, SL, et al. (2014) Brazilin ameliorates high glucose-induced vascular inflammation via inhibiting ROS and CAMs production in human umbilical vein endothelial cells. Biomed Res Int 2014, 403703.
235. Lee, W, Ku, SK, Lee, D, et al. (2014) Emodin-6-O-beta-D – glucoside inhibits high-glucose-induced vascular inflammation. Inflammation 37, 306313.
236. Xiong, Y, Wang, GF, Zhang, JY, et al. (2010) [Naringin inhibits monocyte adhesion to high glucose-induced human umbilical vein endothelial cells]. Nan Fang Yi Ke Da Xue Xue Bao 30, 321325.
237. Kwak, S, Ku, SK & Bae, JS (2014) Fisetin inhibits high-glucose-induced vascular inflammation in vitro and in vivo . Inflamm Res 63, 779787.
238. Ku, SK, Kwak, S & Bae, JS (2014) Orientin inhibits high glucose-induced vascular inflammation in vitro and in vivo . Inflammation 37, 21642173.
239. Ku, SK & Bae, JS (2015) Baicalin, baicalein and wogonin inhibits high glucose-induced vascular inflammation in vitro and in vivo . BMB Rep 48, 519524.
240. Zheng, X, Zhu, S, Chang, S, et al. (2013) Protective effects of chronic resveratrol treatment on vascular inflammatory injury in steptozotocin-induced type 2 diabetic rats: role of NF-kappa B signaling. Eur J Pharmacol 720, 147157.
241. Babu, PV, Si, H, Fu, Z, et al. (2012) Genistein prevents hyperglycemia-induced monocyte adhesion to human aortic endothelial cells through preservation of the cAMP signaling pathway and ameliorates vascular inflammation in obese diabetic mice. J Nutr 142, 724730.
242. Margina, D, Gradinaru, D, Manda, G, et al. (2013) Membranar effects exerted in vitro by polyphenols – quercetin, epigallocatechin gallate and curcumin – on HUVEC and Jurkat cells, relevant for diabetes mellitus. Food Chem Toxicol 61, 8693.
243. Cho, HY, Reddy, SP & Kleeberger, SR (2006) Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 8, 7687.
244. Zhang, DD (2006) Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38, 769789.
245. Chen, XL, Varner, SE, Rao, AS, et al. (2003) Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism. J Biol Chem 278, 703711.
246. Afonyushkin, T, Oskolkova, OV, Philippova, M, et al. (2010) Oxidized phospholipids regulate expression of ATF4 and VEGF in endothelial cells via NRF2-dependent mechanism: novel point of convergence between electrophilic and unfolded protein stress pathways. Arterioscler Thromb Vasc Biol 30, 10071013.
247. Luo, Z, Aslam, S, Welch, WJ, et al. (2015) Activation of nuclear factor erythroid 2-related factor 2 coordinates dimethylarginine dimethylaminohydrolase/PPAR-gamma/endothelial nitric oxide synthase pathways that enhance nitric oxide generation in human glomerular endothelial cells. Hypertension 65, 896902.
248. Zhong, Q, Mishra, M & Kowluru, RA (2013) Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 54, 39413948.
249. Ungvari, Z, Bailey-Downs, L, Gautam, T, et al. (2011) Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol 300, H1133H1140.
250. Suh, JH, Shenvi, SV, Dixon, BM, et al. (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A 101, 33813386.
251. Jiang, T, Huang, Z, Lin, Y, et al. (2010) The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59, 850860.
252. Okouchi, M, Okayama, N, Alexander, JS, et al. (2006) NRF2-dependent glutamate-L-cysteine ligase catalytic subunit expression mediates insulin protection against hyperglycemia- induced brain endothelial cell apoptosis. Curr Neurovasc Res 3, 249261.
253. Yoh, K, Hirayama, A, Ishizaki, K, et al. (2008) Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells 13, 11591170.
254. Ungvari, Z, Bagi, Z, Feher, A, et al. (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299, H18H24.
255. Velmurugan, GV, Sundaresan, NR, Gupta, MP, et al. (2013) Defective Nrf2-dependent redox signalling contributes to microvascular dysfunction in type 2 diabetes. Cardiovasc Res 100, 143150.
256. Lee, SE, Yang, H, Son, GW, et al. (2015) Eriodictyol protects endothelial cells against oxidative stress-induced cell death through modulating ERK/Nrf2/ARE-dependent heme oxygenase-1 expression. Int J Mol Sci 16, 1452614539.
257. Ganesh Yerra, V, Negi, G, Sharma, SS, et al. (2013) Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-kappaB pathways in diabetic neuropathy. Redox Biol 1, 394397.
258. Xue, M, Qian, Q, Adaikalakoteswari, A, et al. (2008) Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 57, 28092817.
259. Negi, G, Kumar, A & Sharma, SS (2011) Nrf2 and NF-kappaB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Curr Neurovasc Res 8, 294304.
260. Kant, V, Gopal, A, Kumar, D, et al. (2015) Curcumin-induced angiogenesis hastens wound healing in diabetic rats. J Surg Res 193, 978988.
261. Babu, PV, Si, H & Liu, D (2012) Epigallocatechin gallate reduces vascular inflammation in db/db mice possibly through an NF-kappaB-mediated mechanism. Mol Nutr Food Res 56, 14241432.
262. Wen, D, Huang, X, Zhang, M, et al. (2013) Resveratrol attenuates diabetic nephropathy via modulating angiogenesis. PLOS ONE 8, e82336.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed