Basic Research in Cardiology

, 107:237 | Cite as

The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update

  • Hanrui Zhang
  • Kevin C. Dellsperger
  • Cuihua Zhang
Invited Review


Despite abundant clinical evidence linking metabolic abnormalities to diabetic vasculopathy, the molecular basis of individual susceptibility to diabetic vascular complications is still largely undetermined. Endothelial dysfunction in diabetes-associated vascular complications is considered an early stage of vasculopathy and has attracted considerable research interests. Type 2 diabetes is characterized by metabolic abnormalities, such as hyperglycemia, excess liberation of free fatty acids (FFA), insulin resistance and hyperinsulinemia. These abnormalities exert pathological impact on endothelial function by attenuating endothelium-mediated vasomotor function, enhancing endothelial apoptosis, stimulating endothelium activation/endothelium–monocyte adhesion, promoting an atherogenic response and suppressing barrier function. There are multiple signaling pathways contributing to the adverse effects of glucotoxicity on endothelial function. Insulin maintains the normal balance for release of several factors with vasoactive properties. Abnormal insulin signaling in the endothelium does not affect the whole-body glucose metabolism, but impairs endothelial response to insulin and accelerates atherosclerosis. Excessive level of FFA is implicated in the pathogenesis of insulin resistance. FFA induces endothelial oxidative stress, apoptosis and inflammatory response, and inhibits insulin signaling. Although hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia independently contribute to endothelial dysfunction via various distinct mechanisms, the mutual interactions may synergistically accelerate their adverse effects. Oxidative stress and inflammation are predicted to be among the first alterations which may trigger other downstream mediators in diabetes associated with endothelial dysfunction. These mechanisms may provide insights into potential therapeutic targets that can delay or reverse diabetic vasculopathy.


Endothelial function Dyslipidemia Hyperglycemia Insulin resistance Inflammation Oxidative stress 



This study was supported by NIH grants (RO1-HL077566 and RO1-HL085119, to C.Z.) and the American Heart Association Predoctoral Fellowship (10PRE4300043 to H.Z.).


  1. 1.
    Anderson RA, Evans LM, Ellis GR, Khan N, Morris K, Jackson SK, Rees A, Lewis MJ, Frenneaux MP (2006) Prolonged deterioration of endothelial dysfunction in response to postprandial lipaemia is attenuated by vitamin C in type 2 diabetes. Diabet Med 23:258–264. doi: 10.1111/j.1464-5491.2005.01767.x PubMedCrossRefGoogle Scholar
  2. 2.
    Artwohl M, Lindenmair A, Sexl V, Maier C, Rainer G, Freudenthaler A, Huttary N, Wolzt M, Nowotny P, Luger A, Baumgartner-Parzer SM (2008) Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells. J Lipid Res 49:2627–2640. doi: 10.1194/jlr.M800393-JLR200 PubMedCrossRefGoogle Scholar
  3. 3.
    Azekoshi Y, Yasu T, Watanabe S, Tagawa T, Abe S, Yamakawa K, Uehara Y, Momomura S, Urata H, Ueda S (2010) Free fatty acid causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells. Hypertension 56:136–142. doi: 10.1161/HYPERTENSIONAHA.110.153056 PubMedCrossRefGoogle Scholar
  4. 4.
    Bakker W, Eringa EC, Sipkema P, van Hinsbergh VW (2009) Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell Tissue Res 335:165–189. doi: 10.1007/s00441-008-0685-6 PubMedCrossRefGoogle Scholar
  5. 5.
    Barrett EJ, Eggleston EM, Inyard AC, Wang H, Li G, Chai W, Liu Z (2009) The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action. Diabetologia 52:752–764. doi: 10.1007/s00125-009-1313-z PubMedCrossRefGoogle Scholar
  6. 6.
    Becker BF, Chappell D, Jacob M (2010) Endothelial glycocalyx and coronary vascular permeability: the fringe benefit. Basic Res Cardiol 105:687–701. doi: 10.1007/s00395-010-0118-z PubMedCrossRefGoogle Scholar
  7. 7.
    Belin de Chantemele EJ, Ali MI, Mintz J, Stepp DW (2009) Obesity induced insulin resistance causes endothelial dysfunction without reducing the vascular response to hindlimb ischemia. Basic Res Cardiol 104:707–717. doi: 10.1007/s00395-009-0042-2 PubMedCrossRefGoogle Scholar
  8. 8.
    Belin de Chantemele EJ, Stepp DW (2011) Influence of obesity and metabolic dysfunction on the endothelial control in the coronary circulation. J Mol Cell Cardiol. doi:10.1016/j.yjmcc.2011.08.018
  9. 9.
    Brouwers O, Niessen PM, Haenen G, Miyata T, Brownlee M, Stehouwer CD, De Mey JG, Schalkwijk CG (2010) Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress. Diabetologia 53:989–1000. doi: 10.1007/s00125-010-1677-0 PubMedCrossRefGoogle Scholar
  10. 10.
    Chai W, Liu Z (2007) p38 mitogen-activated protein kinase mediates palmitate-induced apoptosis but not inhibitor of nuclear factor-kappaB degradation in human coronary artery endothelial cells. Endocrinology 148:1622–1628. doi: 10.1210/en.2006-1068 PubMedCrossRefGoogle Scholar
  11. 11.
    Cheang WS, Wong WT, Tian XY, Yang Q, Lee HK, He GW, Yao X, Huang Y (2011) Endothelial nitric oxide synthase enhancer reduces oxidative stress and restores endothelial function in db/db mice. Cardiovasc Res 92:267–275. doi: 10.1093/cvr/cvr233 PubMedCrossRefGoogle Scholar
  12. 12.
    Chinen I, Shimabukuro M, Yamakawa K, Higa N, Matsuzaki T, Noguchi K, Ueda S, Sakanashi M, Takasu N (2007) Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats. Endocrinology 148:160–165. doi: 10.1210/en.2006-1132 PubMedCrossRefGoogle Scholar
  13. 13.
    Cifarelli V, Geng X, Styche A, Lakomy R, Trucco M, Luppi P (2011) C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells. Diabetologia 54:2702–2712. doi: 10.1007/s00125-011-2251-0 PubMedCrossRefGoogle Scholar
  14. 14.
    Conget I, Gimenez M (2009) Glucose control and cardiovascular disease: is it important? No Diabetes Care 32 Suppl 2:S334–336. doi: 10.2337/dc09-S334
  15. 15.
    Drummond GR, Selemidis S, Griendling KK, Sobey CG (2011) Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov 10:453–471. doi: 10.1038/nrd3403 PubMedCrossRefGoogle Scholar
  16. 16.
    Du X, Edelstein D, Obici S, Higham N, Zou MH, Brownlee M (2006) Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 116:1071–1080. doi: 10.1172/JCI23354 PubMedCrossRefGoogle Scholar
  17. 17.
    Duncan ER, Crossey PA, Walker S, Anilkumar N, Poston L, Douglas G, Ezzat VA, Wheatcroft SB, Shah AM, Kearney MT (2008) Effect of endothelium-specific insulin resistance on endothelial function in vivo. Diabetes 57:3307–3314. doi: 10.2337/db07-1111 PubMedCrossRefGoogle Scholar
  18. 18.
    Edirisinghe I, McCormick Hallam K, Kappagoda CT (2006) Effect of fatty acids on endothelium-dependent relaxation in the rabbit aorta. Clin Sci (Lond) 111:145–151. doi: 10.1042/CS20060001 CrossRefGoogle Scholar
  19. 19.
    Ergul A (2011) Endothelin-1 and diabetic complications: focus on the vasculature. Pharmacol Res 63:477–482. doi: 10.1016/j.phrs.2011.01.012 PubMedCrossRefGoogle Scholar
  20. 20.
    Feletou M, Huang Y, Vanhoutte PM (2011) Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol 164:894–912. doi: 10.1111/j.1476-5381.2011.01276.x PubMedCrossRefGoogle Scholar
  21. 21.
    Feletou M, Vanhoutte PM (2009) EDHF: an update. Clin Sci (Lond) 117:139–155. doi: 10.1042/CS20090096 CrossRefGoogle Scholar
  22. 22.
    Fulton DJ (2009) Mechanisms of vascular insulin resistance: a substitute Akt? Circ Res 104:1035–1037. doi: 10.1161/CIRCRESAHA.109.198028 PubMedCrossRefGoogle Scholar
  23. 23.
    Gao X, Belmadani S, Picchi A, Xu X, Potter BJ, Tewari-Singh N, Capobianco S, Chilian WM, Zhang C (2007) Tumor necrosis factor-alpha induces endothelial dysfunction in Lepr(db) mice. Circulation 115:245–254. doi: 10.1161/CIRCULATIONAHA.106.650671 PubMedCrossRefGoogle Scholar
  24. 24.
    Gao X, Martinez-Lemus LA, Zhang C (2011) Endothelium-derived hyperpolarizing factor and diabetes. World J Cardiol 3:25–31. doi: 10.4330/wjc.v3.i1.25 PubMedCrossRefGoogle Scholar
  25. 25.
    Gao X, Zhang H, Schmidt AM, Zhang C (2008) AGE/RAGE produces endothelial dysfunction in coronary arterioles in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 295:H491–H498. doi: 10.1152/ajpheart.00464.2008 PubMedCrossRefGoogle Scholar
  26. 26.
    Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, Clermont A, Leitges M, Marette A, Aiello LP, Kern TS, King GL (2009) Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med 15:1298–1306. doi: 10.1038/nm.2052 PubMedCrossRefGoogle Scholar
  27. 27.
    Geraldes P, King GL (2010) Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res 106:1319–1331. doi: 10.1161/CIRCRESAHA.110.217117 PubMedCrossRefGoogle Scholar
  28. 28.
    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 58:2238–2245. doi: 10.2337/db08-0961 PubMedCrossRefGoogle Scholar
  29. 29.
    Goodwill AG, James ME, Frisbee JC (2008) Increased vascular thromboxane generation impairs dilation of skeletal muscle arterioles of obese Zucker rats with reduced oxygen tension. Am J Physiol Heart Circ Physiol 295:H1522–H1528. doi: 10.1152/ajpheart.00596.2008 PubMedCrossRefGoogle Scholar
  30. 30.
    Hajer GR, van Haeften TW, Visseren FL (2008) Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 29:2959–2971. doi: 10.1093/eurheartj/ehn387 PubMedCrossRefGoogle Scholar
  31. 31.
    Heusch G (2011) Obesity and inflammatory vasculopathy: a surgical solution as ultima ratio? Arterioscler Thromb Vasc Biol 31:1953–1954. doi: 10.1161/ATVBAHA.111.232264 PubMedCrossRefGoogle Scholar
  32. 32.
    Hodgkinson CP, Laxton RC, Patel K, Ye S (2008) Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler Thromb Vasc Biol 28:2275–2281. doi: 10.1161/ATVBAHA.108.175992 PubMedCrossRefGoogle Scholar
  33. 33.
    Jellinger PS (2007) Metabolic consequences of hyperglycemia and insulin resistance. Clin Cornerstone 8 (Suppl 7):S30–42. doi: 10.1016/S1098-3597(07)80019-6
  34. 34.
    Kador PF, Randazzo J, Blessing K, Makita J, Zhang P, Yu K, Hosoya K, Terasaki T (2009) Polyol formation in cell lines of rat retinal capillary pericytes and endothelial cells (TR-rPCT and TR-iBRB). J Ocul Pharmacol Ther 25:299–308. doi: 10.1089/jop.2008.0070 PubMedCrossRefGoogle Scholar
  35. 35.
    Katz PS, Trask AJ, Souza-Smith FM, Hutchinson KR, Galantowicz ML, Lord KC, Stewart JA Jr, Cismowski MJ, Varner KJ, Lucchesi PA (2011) Coronary arterioles in type 2 diabetic (db/db) mice undergo a distinct pattern of remodeling associated with decreased vessel stiffness. Basic Res Cardiol 106:1123–1134. doi: 10.1007/s00395-011-0201-0 PubMedCrossRefGoogle Scholar
  36. 36.
    Khamaisi M, Dahan R, Hamed S, Abassi Z, Heyman SN, Raz I (2009) Role of protein kinase C in the expression of endothelin converting enzyme-1. Endocrinology 150:1440–1449. doi: 10.1210/en.2008-0524 PubMedCrossRefGoogle Scholar
  37. 37.
    Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW (2005) Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol 25:989–994. doi: 10.1161/01.ATV.0000160549.60980.a8 PubMedCrossRefGoogle Scholar
  38. 38.
    Koh KK, Oh PC, Quon MJ (2009) Does reversal of oxidative stress and inflammation provide vascular protection? Cardiovasc Res 81:649–659. doi: 10.1093/cvr/cvn354 PubMedCrossRefGoogle Scholar
  39. 39.
    Liu J, Jahn LA, Fowler DE, Barrett EJ, Cao W, Liu Z (2011) Free fatty acids induce insulin resistance in both cardiac and skeletal muscle microvasculature in humans. J Clin Endocrinol Metab 96:438–446. doi: 10.1210/jc.2010-1174 PubMedCrossRefGoogle Scholar
  40. 40.
    Lorenzi M (2007) The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp Diabetes Res 2007:61038. doi: 10.1155/2007/61038 PubMedGoogle Scholar
  41. 41.
    Lu X, Bean JS, Kassab GS, Rekhter MD (2011) Protein kinase C inhibition ameliorates functional endothelial insulin resistance and vascular smooth muscle cell hypersensitivity to insulin in diabetic hypertensive rats. Cardiovasc Diabetol 10:48. doi: 10.1186/1475-2840-10-48 PubMedCrossRefGoogle Scholar
  42. 42.
    Manea SA, Manea A, Heltianu C (2010) Inhibition of JAK/STAT signaling pathway prevents high-glucose-induced increase in endothelin-1 synthesis in human endothelial cells. Cell Tissue Res 340:71–79. doi: 10.1007/s00441-010-0936-1 PubMedCrossRefGoogle Scholar
  43. 43.
    Mathew M, Tay E, Cusi K (2010) Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects. Cardiovasc Diabetol 9:9. doi: 10.1186/1475-2840-9-9 PubMedCrossRefGoogle Scholar
  44. 44.
    Matsui-Hirai H, Hayashi T, Yamamoto S, Ina K, Maeda M, Kotani H, Iguchi A, Ignarro LJ, Hattori Y (2011) Dose-dependent modulatory effects of insulin on glucose-induced endothelial senescence in vitro and in vivo: a relationship between telomeres and nitric oxide. J Pharmacol Exp Ther 337:591–599. doi: 10.1124/jpet.110.177584 PubMedCrossRefGoogle Scholar
  45. 45.
    Matsumoto T, Ishida K, Nakayama N, Taguchi K, Kobayashi T, Kamata K (2010) Mechanisms underlying the losartan treatment-induced improvement in the endothelial dysfunction seen in mesenteric arteries from type 2 diabetic rats. Pharmacol Res 62:271–281. doi: 10.1016/j.phrs.2010.03.003 PubMedCrossRefGoogle Scholar
  46. 46.
    Mittermayer F, Schaller G, Pleiner J, Krzyzanowska K, Kapiotis S, Roden M, Wolzt M (2007) Rosiglitazone prevents free fatty acid-induced vascular endothelial dysfunction. J Clin Endocrinol Metab 92:2574–2580. doi: 10.1210/jc.2006-2130 PubMedCrossRefGoogle Scholar
  47. 47.
    Montagnani M, Golovchenko I, Kim I, Koh GY, Goalstone ML, Mundhekar AN, Johansen M, Kucik DF, Quon MJ, Draznin B (2002) Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 277:1794–1799. doi: 10.1074/jbc.M103728200 PubMedCrossRefGoogle Scholar
  48. 48.
    Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ (2002) Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol 16:1931–1942. doi: 10.1210/me.2002-0074 PubMedCrossRefGoogle Scholar
  49. 49.
    Munzel T, Gori T, Bruno RM, Taddei S (2010) Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J 31:2741–2748. doi: 10.1093/eurheartj/ehq396 PubMedCrossRefGoogle Scholar
  50. 50.
    Murdoch CE, Alom-Ruiz SP, Wang M, Zhang M, Walker S, Yu B, Brewer A, Shah AM (2011) Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction. Basic Res Cardiol 106:527–538. doi: 10.1007/s00395-011-0179-7 PubMedCrossRefGoogle Scholar
  51. 51.
    Nakagawa T, Tanabe K, Croker BP, Johnson RJ, Grant MB, Kosugi T, Li Q (2011) Endothelial dysfunction as a potential contributor in diabetic nephropathy. Nat Rev Nephrol 7:36–44. doi: 10.1038/nrneph.2010.152 PubMedCrossRefGoogle Scholar
  52. 52.
    Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M, Meijers JC, Holleman F, Hoekstra JB, Vink H, Kastelein JJ, Stroes ES (2006) Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 55:480–486. doi: 10.2337/diabetes.55.02.06.db05-1103 PubMedCrossRefGoogle Scholar
  53. 53.
    Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790. doi: 10.1038/35008121 PubMedCrossRefGoogle Scholar
  54. 54.
    Oppermann M, Suvorava T, Freudenberger T, Dao VT, Fischer JW, Weber M, Kojda G (2011) Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification. Basic Res Cardiol 106:539–549. doi: 10.1007/s00395-011-0160-5 PubMedCrossRefGoogle Scholar
  55. 55.
    Pannirselvam M, Verma S, Anderson TJ, Triggle CR (2002) Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db -/-) mice: role of decreased tetrahydrobiopterin bioavailability. Br J Pharmacol 136:255–263. doi: 10.1038/sj.bjp.0704683 PubMedCrossRefGoogle Scholar
  56. 56.
    Park Y, Capobianco S, Gao X, Falck JR, Dellsperger KC, Zhang C (2008) Role of EDHF in type 2 diabetes-induced endothelial dysfunction. Am J Physiol Heart Circ Physiol 295:H1982–H1988. doi: 10.1152/ajpheart.01261.2007 PubMedCrossRefGoogle Scholar
  57. 57.
    Park Y, Yang J, Zhang H, Chen X, Zhang C (2011) Effect of PAR2 in regulating TNF-alpha and NAD(P)H oxidase in coronary arterioles in type 2 diabetic mice. Basic Res Cardiol 106:111–123. doi: 10.1007/s00395-010-0129-9 PubMedCrossRefGoogle Scholar
  58. 58.
    Perrone L, Devi TS, Hosoya K, Terasaki T, Singh LP (2009) Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions. J Cell Physiol 221:262–272. doi: 10.1002/jcp.21852 PubMedCrossRefGoogle Scholar
  59. 59.
    Piro S, Spampinato D, Spadaro L, Oliveri CE, Purrello F, Rabuazzo AM (2008) Direct apoptotic effects of free fatty acids on human endothelial cells. Nutr Metab Cardiovasc Dis 18:96–104. doi: 10.1016/j.numecd.2007.01.009 PubMedCrossRefGoogle Scholar
  60. 60.
    Potenza MA, Gagliardi S, Nacci C, Carratu MR, Montagnani M (2009) Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. Curr Med Chem 16:94–112PubMedCrossRefGoogle Scholar
  61. 61.
    Rask-Madsen C, Li Q, Freund B, Feather D, Abramov R, Wu IH, Chen K, Yamamoto-Hiraoka J, Goldenbogen J, Sotiropoulos KB, Clermont A, Geraldes P, Dall’Osso C, Wagers AJ, Huang PL, Rekhter M, Scalia R, Kahn CR, King GL (2010) Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab 11:379–389. doi: 10.1016/j.cmet.2010.03.013 PubMedCrossRefGoogle Scholar
  62. 62.
    Reiss K, Cornelsen I, Husmann M, Gimpl G, Bhakdi S (2011) Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity. J Biol Chem 286:26931–26942. doi: 10.1074/jbc.M111.243485 PubMedCrossRefGoogle Scholar
  63. 63.
    Rodino-Janeiro BK, Gonzalez-Peteiro M, Ucieda-Somoza R, Gonzalez-Juanatey JR, Alvarez E (2010) Glycated albumin, a precursor of advanced glycation end-products, up-regulates NADPH oxidase and enhances oxidative stress in human endothelial cells: molecular correlate of diabetic vasculopathy. Diabetes Metab Res Rev 26:550–558. doi: 10.1002/dmrr.1117 PubMedCrossRefGoogle Scholar
  64. 64.
    Sanchez A, Contreras C, Martinez P, Villalba N, Benedito S, Garcia-Sacristan A, Salaices M, Hernandez M, Prieto D (2010) Enhanced cyclooxygenase 2-mediated vasorelaxation in coronary arteries from insulin-resistant obese Zucker rats. Atherosclerosis 213:392–399. doi: 10.1016/j.atherosclerosis.2010.09.022 PubMedCrossRefGoogle Scholar
  65. 65.
    Schalkwijk CG, Stehouwer CD (2005) Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 109:143–159. doi: 10.1042/CS20050025 CrossRefGoogle Scholar
  66. 66.
    Shi Y, Vanhoutte PM (2009) Reactive oxygen-derived free radicals are key to the endothelial dysfunction of diabetes. J Diabetes 1:151–162. doi: 10.1111/j.1753-0407.2009.00030.x PubMedCrossRefGoogle Scholar
  67. 67.
    Souza-Smith FM, Katz PS, Trask AJ, Stewart JA Jr, Lord KC, Varner KJ, Vassallo DV, Lucchesi PA (2011) Mesenteric resistance arteries in Type 2 diabetic db/db mice undergo outward remodeling. PLoS One 6:e23337. doi: 10.1371/journal.pone.0023337 PubMedCrossRefGoogle Scholar
  68. 68.
    Staiger K, Staiger H, Weigert C, Haas C, Haring HU, Kellerer M (2006) Saturated, but not unsaturated, fatty acids induce apoptosis of human coronary artery endothelial cells via nuclear factor-kappaB activation. Diabetes 55:3121–3126. doi: 10.2337/db06-0188 PubMedCrossRefGoogle Scholar
  69. 69.
    Symons JD, Hu P, Yang Y, Wang X, Zhang QJ, Wende AR, Sloan CL, Sena S, Abel ED, Litwin SE (2011) Knockout of insulin receptors in cardiomyocytes attenuates coronary arterial dysfunction induced by pressure overload. Am J Physiol Heart Circ Physiol 300:H374–H381. doi: 10.1152/ajpheart.01200.2009 PubMedCrossRefGoogle Scholar
  70. 70.
    Symons JD, McMillin SL, Riehle C, Tanner J, Palionyte M, Hillas E, Jones D, Cooksey RC, Birnbaum MJ, McClain DA, Zhang QJ, Gale D, Wilson LJ, Abel ED (2009) Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure. Circ Res 104:1085–1094. doi: 10.1161/CIRCRESAHA.108.189316 PubMedCrossRefGoogle Scholar
  71. 71.
    Tabit CE, Chung WB, Hamburg NM, Vita JA (2010) Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endocr Metab Disord 11:61–74. doi: 10.1007/s11154-010-9134-4 PubMedCrossRefGoogle Scholar
  72. 72.
    Tack CJ, Ong MK, Lutterman JA, Smits P (1998) Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia 41:569–576. doi: 10.1007/s001250050948 PubMedCrossRefGoogle Scholar
  73. 73.
    Taye A, Saad AH, Kumar AH, Morawietz H (2010) Effect of apocynin on NADPH oxidase-mediated oxidative stress-LOX-1-eNOS pathway in human endothelial cells exposed to high glucose. Eur J Pharmacol 627:42–48. doi: 10.1016/j.ejphar.2009.10.045 PubMedCrossRefGoogle Scholar
  74. 74.
    Tilg H, Moschen AR (2008) Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 14:222–231. doi: 10.2119/2007-00119.Tilg PubMedCrossRefGoogle Scholar
  75. 75.
    Tiyerili V, Zimmer S, Jung S, Wassmann K, Naehle CP, Lutjohann D, Zimmer A, Nickenig G, Wassmann S (2010) CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function. Basic Res Cardiol 105:465–477. doi: 10.1007/s00395-010-0090-7 PubMedCrossRefGoogle Scholar
  76. 76.
    Toth E, Racz A, Toth J, Kaminski PM, Wolin MS, Bagi Z, Koller A (2007) Contribution of polyol pathway to arteriolar dysfunction in hyperglycemia. Role of oxidative stress, reduced NO, and enhanced PGH(2)/TXA(2) mediation. Am J Physiol Heart Circ Physiol 293:H3096–3104. doi: 10.1152/ajpheart.01335.2006 Google Scholar
  77. 77.
    Uemura S, Matsushita H, Li W, Glassford AJ, Asagami T, Lee KH, Harrison DG, Tsao PS (2001) Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress. Circ Res 88:1291–1298. doi: 10.1161/hh1201.092042 PubMedCrossRefGoogle Scholar
  78. 78.
    Umpierrez GE, Smiley D, Robalino G, Peng L, Kitabchi AE, Khan B, Le A, Quyyumi A, Brown V, Phillips LS (2009) Intravenous intralipid-induced blood pressure elevation and endothelial dysfunction in obese African-Americans with type 2 diabetes. J Clin Endocrinol Metab 94:609–614. doi: 10.1210/jc.2008-1590 PubMedCrossRefGoogle Scholar
  79. 79.
    Vanhoutte PM, Shimokawa H, Tang EH, Feletou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196:193–222. doi: 10.1111/j.1748-1716.2009.01964.x CrossRefGoogle Scholar
  80. 80.
    Vanhoutte PM, Tang EH (2008) Endothelium-dependent contractions: when a good guy turns bad! J Physiol 586:5295–5304. doi: 10.1113/jphysiol.2008.161430 PubMedCrossRefGoogle Scholar
  81. 81.
    Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, Bursell S, Yanagisawa M, King GL, Kahn CR (2003) The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J Clin Invest 111:1373–1380. doi: 10.1172/JCI15211 PubMedGoogle Scholar
  82. 82.
    Wang H, Li H, Hou Z, Pan L, Shen X, Li G (2009) Role of oxidative stress in elevated blood pressure induced by high free fatty acids. Hypertens Res 32:152–158. doi: 10.1038/hr.2008.35 PubMedCrossRefGoogle Scholar
  83. 83.
    Wang XL, Zhang L, Youker K, Zhang MX, Wang J, LeMaire SA, Coselli JS, Shen YH (2006) Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes 55:2301–2310. doi: 10.2337/db05-1574 PubMedCrossRefGoogle Scholar
  84. 84.
    Wang Y, Cheng KK, Lam KS, Wu D, Huang Y, Vanhoutte PM, Sweeney G, Li Y, Xu A (2011) APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice. Diabetes 60:3044–3054. doi: 10.2337/db11-0666 PubMedCrossRefGoogle Scholar
  85. 85.
    Warboys CM, Toh HB, Fraser PA (2009) Role of NADPH oxidase in retinal microvascular permeability increase by RAGE activation. Invest Ophthalmol Vis Sci 50:1319–1328. doi: 10.1167/iovs.08-2730 PubMedCrossRefGoogle Scholar
  86. 86.
    Watanabe S, Tagawa T, Yamakawa K, Shimabukuro M, Ueda S (2005) Inhibition of the renin–angiotensin system prevents free fatty acid-induced acute endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol 25:2376–2380. doi: 10.1161/01.ATV.0000187465.55507.85 PubMedCrossRefGoogle Scholar
  87. 87.
    Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115:1111–1119. doi: 10.1172/JCI25102 PubMedGoogle Scholar
  88. 88.
    Wong MS, Vanhoutte PM (2010) COX-mediated endothelium-dependent contractions: from the past to recent discoveries. Acta Pharmacol Sin 31:1095–1102. doi: 10.1038/aps.2010.127 PubMedCrossRefGoogle Scholar
  89. 89.
    Wu Y, Feng B, Chen S, Zuo Y, Chakrabarti S (2010) Glucose-induced endothelin-1 expression is regulated by ERK5 in the endothelial cells and retina of diabetic rats. Can J Physiol Pharmacol 88:607–615. doi: 10.1139/Y10-033 PubMedCrossRefGoogle Scholar
  90. 90.
    Xue M, Qian Q, Adaikalakoteswari A, Rabbani N, Babaei-Jadidi R, Thornalley PJ (2008) Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 57:2809–2817. doi: 10.2337/db06-1003 PubMedCrossRefGoogle Scholar
  91. 91.
    Yang J, Park Y, Zhang H, Gao X, Wilson E, Zimmer W, Abbott L, Zhang C (2009) Role of MCP-1 in tumor necrosis factor-alpha-induced endothelial dysfunction in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 297:H1208–H1216. doi: 10.1152/ajpheart.00396.2009 PubMedCrossRefGoogle Scholar
  92. 92.
    Yang Z, Li JC (2008) Stimulation of endothelin-1 gene expression by insulin via phosphoinositide-3 kinase-glycogen synthase kinase-3beta signaling in endothelial cells. Life Sci 82:512–518. doi: 10.1016/j.lfs.2007.12.005 PubMedCrossRefGoogle Scholar
  93. 93.
    Yao D, Brownlee M (2010) Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes 59:249–255. doi: 10.2337/db09-0801 PubMedCrossRefGoogle Scholar
  94. 94.
    Ye Y, Perez-Polo JR, Aguilar D, Birnbaum Y (2011) The potential effects of anti-diabetic medications on myocardial ischemia–reperfusion injury. Basic Res Cardiol 106:925–952. doi: 10.1007/s00395-011-0216-6 PubMedCrossRefGoogle Scholar
  95. 95.
    Yu Q, Gao F, Ma XL (2011) Insulin says NO to cardiovascular disease. Cardiovasc Res 89:516–524. doi: 10.1093/cvr/cvq349 PubMedCrossRefGoogle Scholar
  96. 96.
    Zeng G, Nystrom FH, Ravichandran LV, Cong LN, Kirby M, Mostowski H, Quon MJ (2000) Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 101:1539–1545PubMedGoogle Scholar
  97. 97.
    Zhang C, Wu J, Xu X, Potter BJ, Gao X (2010) Direct relationship between levels of TNF-alpha expression and endothelial dysfunction in reperfusion injury. Basic Res Cardiol 105:453–464. doi: 10.1007/s00395-010-0083-6 PubMedCrossRefGoogle Scholar
  98. 98.
    Zhang H, Potter BJ, Cao JM, Zhang C (2011) Interferon-gamma induced adipose tissue inflammation is linked to endothelial dysfunction in type 2 diabetic mice. Basic Res Cardiol 106:1135–1145. doi: 10.1007/s00395-011-0212-x PubMedCrossRefGoogle Scholar
  99. 99.
    Zhang H, Wang Y, Zhang J, Potter BJ, Sowers JR, Zhang C (2011) Bariatric surgery reduces visceral adipose inflammation and improves endothelial function in type 2 diabetic mice. Arterioscler Thromb Vasc Biol 31:2063–2069. doi: 10.1161/ATVBAHA.111.225870 PubMedCrossRefGoogle Scholar
  100. 100.
    Zhang H, Zhang C (2010) Adipose “talks” to distant organs to regulate insulin sensitivity and vascular function. Obesity (Silver Spring) 18:2071–2076. doi: 10.1038/oby.2010.91 CrossRefGoogle Scholar
  101. 101.
    Zhang H, Zhang C (2009) Regulation of microvascular function by adipose tissue in obesity and Type 2 diabetes: evidence of an adipose-vascular loop. Am J Biomed Sci 1:133–142. doi: 10.5099/aj090200133 PubMedCrossRefGoogle Scholar
  102. 102.
    Zhang H, Zhang J, Ungvari Z, Zhang C (2009) Resveratrol improves endothelial function: role of TNF{alpha} and vascular oxidative stress. Arterioscler Thromb Vasc Biol 29:1164–1171. doi: 10.1161/ATVBAHA.109.187146 PubMedCrossRefGoogle Scholar
  103. 103.
    Zhang LN, Vincelette J, Chen D, Gless RD, Anandan SK, Rubanyi GM, Webb HK, MacIntyre DE, Wang YX (2011) Inhibition of soluble epoxide hydrolase attenuates endothelial dysfunction in animal models of diabetes, obesity and hypertension. Eur J Pharmacol 654:68–74. doi: 10.1016/j.ejphar.2010.12.016 PubMedCrossRefGoogle Scholar
  104. 104.
    Zhang Q, Malik P, Pandey D, Gupta S, Jagnandan D, Belin de Chantemele E, Banfi B, Marrero MB, Rudic RD, Stepp DW, Fulton DJ (2008) Paradoxical activation of endothelial nitric oxide synthase by NADPH oxidase. Arterioscler Thromb Vasc Biol 28:1627–1633. doi: 10.1161/ATVBAHA.108.168278 PubMedCrossRefGoogle Scholar
  105. 105.
    Zhang WY, Schwartz E, Wang Y, Attrep J, Li Z, Reaven P (2006) Elevated concentrations of nonesterified fatty acids increase monocyte expression of CD11b and adhesion to endothelial cells. Arterioscler Thromb Vasc Biol 26:514–519. doi: 10.1161/01.ATV.0000200226.53994.09 PubMedCrossRefGoogle Scholar
  106. 106.
    Zhou H, Liu X, Liu L, Yang Z, Zhang S, Tang M, Tang Y, Dong Q, Hu R (2009) Oxidative stress and apoptosis of human brain microvascular endothelial cells induced by free fatty acids. J Int Med Res 37:1897–1903PubMedGoogle Scholar
  107. 107.
    Zhu P, Chen G, You T, Yao J, Jiang Q, Lin X, Shen X, Qiao Y, Lin L (2010) High FFA-induced proliferation and apoptosis in human umbilical vein endothelial cell partly through Wnt/beta-catenin signal pathway. Mol Cell Biochem 338:123–131. doi: 10.1007/s11010-009-0345-5 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Hanrui Zhang
    • 1
  • Kevin C. Dellsperger
    • 2
  • Cuihua Zhang
    • 1
  1. 1.Departments of Internal Medicine, Medical Pharmacology & Physiology and Nutritional Sciences, Dalton Cardiovascular Research CenterUniversity of Missouri-ColumbiaColumbiaUSA
  2. 2.Departments of Internal Medicine and Medical Pharmacology and PhysiologyUniversity of Missouri-ColumbiaColumbiaUSA

Personalised recommendations