Current Hypertension Reports

, Volume 7, Issue 2, pp 88–95 | Cite as

Metabolic syndrome and endothelial dysfunction

  • Alessia Fornoni
  • Leopoldo Raij


The incidence of metabolic syndrome is rapidly increasing in the United States. Metabolic syndrome is associated with increased cardiovascular morbidity and mortality, and endothelial dysfunction is an early pathogenetic event in the metabolic syndrome. Endothelial dysfunction of either the coronary, the peripheral, or the cerebral vasculature is a predictor of vascular events and appears to be a marker of uncontrolled atherosclerotic risk that adds to the burden of the genetic predisposition to cardiovascular disease. Clinically and experimentally, endothelial dysfunction can be restored by several agents, including blockers/inhibitors of the renin-angiotensin-aldosterone system, as well as statins. Nevertheless, it would be premature, and most likely inappropriate, to use improvement of endothelial function as a surrogate end point to predict reduction in cardiovascular morbidity and mortality. However, a clear understanding of the mechanisms of endothelial dysfunction in the metabolic syndrome may allow the development of preventive and early therapeutic measures targeting cardiovascular disease.


Insulin Resistance Metabolic Syndrome Endothelial Dysfunction Endothelial Function Arterioscler Thromb Vasc Biol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988, 37:1595–1607.PubMedCrossRefGoogle Scholar
  2. 2.
    National Cholesterol Education Program (NCEP): Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002, 106:3143–3421.Google Scholar
  3. 3.
    Enzi, G, Busetto, L, Inelmen, EM, et al.: Historical perspective: visceral obesity and related comorbidity in Joannes Baptista Morgagni’s ‘De sedibus et causis morborum per anatomen Indagata’. Int J Obes Relat Metab Disord 2003, 27:534–535.PubMedCrossRefGoogle Scholar
  4. 4.
    Lakka HM, Laaksonen DE, Lakka TA, et al.: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002, 288:2709–2716.PubMedCrossRefGoogle Scholar
  5. 5.
    Suwaidi JA, Hamasaki S, Higano ST, et al.: Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000, 101:948–954.PubMedGoogle Scholar
  6. 6.
    Palmer RM, Ashton DS, Moncada S: Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988, 333:664–666.PubMedCrossRefGoogle Scholar
  7. 7.
    Yki-Jarvinen H: Insulin resistance and endothelial dysfunction. Best Pract Res Clin Endocrinol Metab 2003, 17:411–430.PubMedCrossRefGoogle Scholar
  8. 8.
    Andrews HE, Bruckdorfer KR, Dunn RC, Jacobs M: Low-density lipoproteins inhibit endothelium-dependent relaxation in rabbit aorta. Nature 1987, 327:237–239.PubMedCrossRefGoogle Scholar
  9. 9.
    Gerstein HC, Mann JF, Yi Q, et al.: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001, 286:421–426.PubMedCrossRefGoogle Scholar
  10. 10.
    Baron AD: Insulin and the vasculature—old actors, new roles. J Investig Med 1996, 44:406–412.PubMedGoogle Scholar
  11. 11.
    Dimmeler S, Fleming I, Fisslthaler B, et al.: Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999, 399:601–605.PubMedCrossRefGoogle Scholar
  12. 12.
    Zeng G, Nystrom FH, Ravichandran LV, et al.: Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 2000, 101:1539–1545.PubMedGoogle Scholar
  13. 13.
    Steinberg HO, Brechtel G, Johnson A, et al.: Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Investig 1994, 94:1172–1179.PubMedGoogle Scholar
  14. 14.
    Gnudi L, Viberti G, Raij L, et al.: GLUT-1 overexpression: link between hemodynamic and metabolic factors in glomerular injury? Hypertension 2003, 42:19–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Abe H, Yamada N, Kamata K, et al.: Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1. J Clin Investig 1998, 101:1784–1788.PubMedGoogle Scholar
  16. 16.
    Huang PL, Huang Z, Mashimo H, et al.: Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995, 377:239–242.PubMedCrossRefGoogle Scholar
  17. 17.
    Sasaoka T, Ishiki M, Sawa T, et al.: Comparison of the insulin and insulin-like growth factor 1 mitogenic intracellular signaling pathways. Endocrinology 1996, 137:4427–4434.PubMedCrossRefGoogle Scholar
  18. 18.
    Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M: Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 2000, 20:2175–2183.PubMedGoogle Scholar
  19. 19.
    Cusi K, Maezono K, Osman A, et al.: Insulin resistance differentially affects the PI 3-kinase-and MAP kinase-mediated signaling in human muscle. J Clin Investig 2000, 105:311–320. The authors showed that insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. They also showed that insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects, proving the importance of the PI3-kinase pathway in ED in humans.PubMedGoogle Scholar
  20. 20.
    Montagnani M, Golovchenko I, Kim I, et al.: Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 2002, 277:1794–1799.PubMedCrossRefGoogle Scholar
  21. 21.
    Pessin JE, Saltiel AR: Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Investig 2000, 106:165–169.PubMedGoogle Scholar
  22. 22.
    Arcaro G, Cretti A, Balzano S, et al.: Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 2002, 105:576–582.PubMedCrossRefGoogle Scholar
  23. 23.
    Campia U, Sullivan G, Bryant MB, et al.: Insulin impairs endothelium-dependent vasodilation independent of insulin sensitivity or lipid profile. Am J Physiol Heart Circ Physiol 2004, 286:H76-H82.PubMedCrossRefGoogle Scholar
  24. 24.
    Hirosumi J, Tuncman G, Chang L, et al.: A central role for JNK in obesity and insulin resistance. Nature 2002, 420:333–336.PubMedCrossRefGoogle Scholar
  25. 25.
    Steinberg HO, Chaker H, Leaming R, et al.: Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Investig 1996, 97:2601–2611.PubMedGoogle Scholar
  26. 26.
    Tounian P, Aggoun Y, Dubern B, et al.: Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet 2001, 358:1400–1404.PubMedCrossRefGoogle Scholar
  27. 27.
    Benjamin EJ, Larson MG, Keyes MJ, et al.: Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation 2004, 109:613–619.PubMedCrossRefGoogle Scholar
  28. 28.
    Sironi AM, Gastaldelli A, Mari A, et al.: Visceral fat in hypertension: influence on insulin resistance and beta-cell function. Hypertension 2004, 44:127–133. The authors clearly showed, in this elegant human study, an important quantitative relation between visceral fat, elevation of blood pressure, and severity of insulin resistance, independent of any effect on β-cell function.PubMedCrossRefGoogle Scholar
  29. 29.
    Steinberg HO, Tarshoby M, Monestel R, et al.: Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Investig 1997, 100:1230–1239.PubMedGoogle Scholar
  30. 30.
    Gumbiner B, Mucha JF, Lindstrom JE, et al.: Differential effects of acute hypertriglyceridemia on insulin action and insulin receptor autophosphorylation. Am J Physiol 1996, 270:E424-E429.PubMedGoogle Scholar
  31. 31.
    Bhagat K, Vallance P: Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. Circulation 1997, 96:3042–3047.PubMedGoogle Scholar
  32. 32.
    Barton M, Carmona R, Morawietz H, et al.: Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin. Hypertension 2000, 35:329–336.PubMedGoogle Scholar
  33. 33.
    Tiret L, Poirier O, Hallet V, et al.: The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension 1999, 33:1169–1174.PubMedGoogle Scholar
  34. 34.
    Quehenberger P, Exner M, Sunder-Plassmann R, et al.: Leptin induces endothelin-1 in endothelial cells in vitro. Circ Res 2002, 90:711–718.PubMedCrossRefGoogle Scholar
  35. 35.
    Lembo G, Vecchione C, Fratta L, et al.: Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes 2000, 49:293–297.PubMedCrossRefGoogle Scholar
  36. 36.
    Shimabukuro M, Higa N, Asahi T, et al.: Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 2003, 88:3236–3240.PubMedCrossRefGoogle Scholar
  37. 37.
    Tsuchida A, Yamauchi T, Ito Y, et al.: Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem 2004, 279:30817–30822.PubMedCrossRefGoogle Scholar
  38. 38.
    Kubota N, Terauchi Y, Yamauchi T, et al.: Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chemistry 2002, 277:25863–25866.CrossRefGoogle Scholar
  39. 39.
    Ouchi N, Ohishi M, Kihara S, et al.: Association of hypoadiponectinemia with impaired vasoreactivty. Hypertension 2003, 42:231–234.PubMedCrossRefGoogle Scholar
  40. 40.
    Steppan CM, Bailey ST, Bhat S, et al.: The hormone resistin links obesity to diabetes. Nature 2001, 409:307–312.PubMedCrossRefGoogle Scholar
  41. 41.
    Lundman P, Eriksson MJ, Silveira A, et al.: Relation of hypertriglyceridemia to plasma concentrations of biochemical markers of inflammation and endothelial activation (C-reactive protein, interleukin-6, soluble adhesion molecules, von Willebrand factor, and endothelin-1). Am J Cardiol 2003, 91:1128–1131.PubMedCrossRefGoogle Scholar
  42. 42.
    Naderali EK, Williams G: Prolonged endothelial-dependent and -independent arterial dysfunction induced in the rat by short-term feeding with a high-fat, high-sucrose diet. Atherosclerosis 2003, 166:253–259.PubMedCrossRefGoogle Scholar
  43. 43.
    Lundman P, Eriksson M, Schenck-Gustafsson K, et al.: Transient triglyceridemia decreases vascular reactivity in young, healthy men without risk factors for coronary heart disease. Circulation 1997, 96:3266–3268.PubMedGoogle Scholar
  44. 44.
    Chowienczyk PJ, Watts GF, Wierzbicki AS, et al.: Preserved endothelial function in patients with severe hypertriglyceridemia and low functional lipoprotein lipase activity. J Am Coll Cardiol 1997, 29:964–968.PubMedCrossRefGoogle Scholar
  45. 45.
    Anderson TJ, Meredith IT, Charbonneau F, et al.: Endotheliumdependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans. Circulation 1996, 93:1647–1650.PubMedGoogle Scholar
  46. 46.
    Creager MA, Cooke JP, Mendelsohn ME, et al.: Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Investig 1990, 86:228–234.PubMedGoogle Scholar
  47. 47.
    Uittenbogaard A, Shaul PW, Yuhanna IS, et al.: High density lipoprotein prevents oxidized low density lipoproteininduced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae. J Biol Chem 2000, 275:11278–11283.PubMedCrossRefGoogle Scholar
  48. 48.
    Bisoendial RJ, Hovingh GK, Levels JH, et al.: Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein. Circulation 2003, 107:2944–2948.PubMedCrossRefGoogle Scholar
  49. 49.
    Tesfamariam B, Cohen RA: Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 1992, 263:H321-H326.PubMedGoogle Scholar
  50. 50.
    Bucala R, Tracey KJ, Cerami A: Advanced glycosylation products quench nitric oxide and mediate defective endotheliumdependent vasodilatation in experimental diabetes. J Clin Investig 1991, 87:432–438.PubMedGoogle Scholar
  51. 51.
    Blair A, Shaul PW, Yuhanna IS, et al.: Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J Biol Chem 1999, 274:32512–32519.PubMedCrossRefGoogle Scholar
  52. 52.
    Nickenig G, Sachinidis A, Michaelsen F, et al.: Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells. Circulation 1997, 95:473–478.PubMedGoogle Scholar
  53. 53.
    Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 1996, 271:C1424-C1437.PubMedGoogle Scholar
  54. 54.
    Zou MH, Shi C, Cohen RA: Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Investig 2002, 109:817–826.PubMedCrossRefGoogle Scholar
  55. 55.
    Katusic ZS: Vascular endothelial dysfunction: Does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol 2001, 281:H981-H986.PubMedGoogle Scholar
  56. 56.
    Cox DA, Vita JA, Treasure CB, et al.: Atherosclerosis impairs flow-mediated dilation of coronary arteries in humans. Circulation 1989, 80:458–465.PubMedGoogle Scholar
  57. 57.
    Panza JA, Quyyumi AA, Brush JE Jr, Epstein, SE: Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990, 323:22–27.PubMedCrossRefGoogle Scholar
  58. 58.
    Bigazzi R, Bianchi S, Baldari D, et al.: Microalbuminuria in salt-sensitive patients: a marker for renal and cardiovascular risk factors. Hypertension 1994, 23:195–199.PubMedGoogle Scholar
  59. 59.
    Zhou MS, Adam AG, Jaimes EA, Raij L: In salt-sensitive hypertension, increased superoxide production is linked to functional upregulation of angiotensin II. Hypertension 2003, 42:945–951.PubMedCrossRefGoogle Scholar
  60. 60.
    Kobori H, Nishiyama A, Abe Y, Navar LG: Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet. Hypertension 2003, 41:592–597.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhou MS, Jaimes EA, Raij L: Inhibition of oxidative stress and improvement of endothelial function by amlodipine in angiotensin II-infused rats. Am J Hypertension 2004, 17:167–171. The authors found that blockade of the AT1 receptor can restore ED without improving blood pressure, suggesting that ED is not a critical factor in the genesis and /or maintenance of hypertension.CrossRefGoogle Scholar
  62. 62.
    Rajagopalan S, Kurz S, Munzel T, et al.: Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Investig 1996, 97:1916–1923.PubMedCrossRefGoogle Scholar
  63. 63.
    Schiffrin EL, Touyz RM: Multiple actions of angiotensin II in hypertension: benefits of AT1 receptor blockade. J Am Coll Cardiol 2003, 42:911–913.PubMedCrossRefGoogle Scholar
  64. 64.
    Chen XL, Tummala PE, Olbrych MT, et al.: Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. Circ Res 1998, 83:952–959.PubMedGoogle Scholar
  65. 65.
    Shinozaki K, Ayajiki K, Nishio Y, et al.: Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension 2004, 43:255–262.PubMedCrossRefGoogle Scholar
  66. 66.
    Park JY, Takahara N, Gabriele A, et al.: Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation. Diabetes 2000, 49:1239–1248.PubMedCrossRefGoogle Scholar
  67. 67.
    Zhang L, Zalewski A, Liu Y, et al.: Diabetes-induced oxidative stress and low-grade inflammation in porcine coronary arteries. Circulation 2003, 108:472–478.PubMedCrossRefGoogle Scholar
  68. 68.
    Mykkanen L, Zaccaro DJ, Wagenknecht LE, et al.: Microalbuminuria is associated with insulin resistance in nondiabetic subjects: the insulin resistance atherosclerosis study. Diabetes 1998, 47:793–800.PubMedCrossRefGoogle Scholar
  69. 69.
    Clausen P, Jensen JS, Jensen G, et al.: Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects. Circulation 2001, 103:1869–1874.PubMedGoogle Scholar
  70. 70.
    Boger RH, Bode-Boger SM, Szuba A, et al.: Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998, 98:1842–1847.PubMedGoogle Scholar
  71. 71.
    Dayoub H, Achan V, Adimoolam S, et al.: Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 2003, 108:3042–3047.PubMedCrossRefGoogle Scholar
  72. 72.
    Waring WS, Adwani SH, Breukels O, et al.: Hyperuricaemia does not impair cardiovascular function in healthy adults. Heart 2004, 90:155–159.PubMedCrossRefGoogle Scholar
  73. 73.
    Jaimes EA, DeMaster EG, Tian RX, Raij L: Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation. Arterioscler Thromb Vasc Biol 2004, 24:1031–1036.PubMedCrossRefGoogle Scholar
  74. 74.
    Ziccardi P, Nappo F, Giugliano G, et al.: Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002, 105:804–809.PubMedCrossRefGoogle Scholar
  75. 75.
    Hamdy O, Ledbury S, Mullooly C, et al.: Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care 2003, 26:2119–2125.PubMedCrossRefGoogle Scholar
  76. 76.
    Klein S, Fontana L, Young VL, et al.: Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med 2004, 350:2549–2557. The authors clearly prove the importance of visceral fat rather than subcutaneous fat in CV risk.PubMedCrossRefGoogle Scholar
  77. 77.
    Knowler WC, Barrett-Connor E, Fowler SE, et al.: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002, 346:393–403.PubMedCrossRefGoogle Scholar
  78. 78.
    Caballero AE, Saouaf R, Lim SC, et al.: The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo-controlled randomized clinical trial. Metab Clin Exper 2003, 52:173–180.Google Scholar
  79. 79.
    Hsueh WA, Law RE: PPARgamma and atherosclerosis: effects on cell growth and movement. Arterioscler Thromb Vasc Biol 2001, 21:1891–1895.PubMedGoogle Scholar
  80. 80.
    Mather KJ, Verma S, Anderson TJ: Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 2001, 37:1344–1350.PubMedCrossRefGoogle Scholar
  81. 81.
    Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998, 352:854–865.Google Scholar
  82. 82.
    Gaenzer H, Neumayr G, Marschang P, et al.: Effect of insulin therapy on endothelium-dependent dilation in type 2 diabetes mellitus. Am J Cardiol 2002, 89:431–434.PubMedCrossRefGoogle Scholar
  83. 83.
    Devereux RB, Roman MJ, Palmieri V, et al.: Left ventricular wall stresses and wall stress-mass-heart rate products in hypertensive patients with electrocardiographic left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint reduction in hypertension. J Hypertens 2000, 18:1129–1138.PubMedCrossRefGoogle Scholar
  84. 84.
    Dagenais GR, Yusuf S, Bourassa MG, et al.: Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 2001, 104:522–526.PubMedGoogle Scholar
  85. 85.
    Julius S, Kjeldsen SE, Weber M, et al.: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004, 393:2022–2031.CrossRefGoogle Scholar
  86. 86.
    Nawano M, Anai M, Funaki M, et al.: Imidapril, an angiotensin-converting enzyme inhibitor, improves insulin sensitivity by enhancing signal transduction via insulin receptor substrate proteins and improving vascular resistance in the Zucker fatty rat. Metab Clin Exper 1999, 48:1248–1255.Google Scholar
  87. 87.
    Yusuf S, Sleight P, Pogue J, et al.: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000, 342:145–153.PubMedCrossRefGoogle Scholar
  88. 88.
    Wassmann S, Hilgers S, Laufs U, et al.: Angiotensin II type 1 receptor antagonism improves hypercholesterolemia-associated endothelial dysfunction. Arterioscler Thromb Vasc Biol 2002, 22:1208–1212.PubMedCrossRefGoogle Scholar
  89. 89.
    Laufs U, La Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998, 97:1129–1135.PubMedGoogle Scholar
  90. 90.
    Cannon CP, Braunwald E, McCabe CH, et al.: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004, 350:1495–1504.PubMedCrossRefGoogle Scholar
  91. 91.
    van Etten RW, de Koning EJ, Honing ML, et al.: Intensive lipid lowering by statin therapy does not improve vasoreactivity in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 2002, 22:799–804.PubMedCrossRefGoogle Scholar
  92. 92.
    van Venrooij FV, van de Ree MA, Bots ML, et al.: Aggressive lipid lowering does not improve endothelial function in type 2 diabetes: the Diabetes Atorvastatin Lipid Intervention (DALI) Study: a randomized, double-blind, placebo-controlled trial. Diabetes Care 2002, 25:1211–1216.PubMedCrossRefGoogle Scholar
  93. 93.
    Sever PS, Dahlof B, Poulter NR, et al.: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.[see comment]. Lancet 2003, 361:1149–1158.PubMedCrossRefGoogle Scholar
  94. 94.
    Colhoun HM, Betteridge DJ, Durrington PN, et al.: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004, 364:685–696.PubMedCrossRefGoogle Scholar
  95. 95.
    Avogaro A, Miola M, Favaro A, et al.: Gemfibrozil improves insulin sensitivity and flow-mediated vasodilatation in type 2 diabetic patients. Eur J Clin Investig 2001, 31:603–609.CrossRefGoogle Scholar
  96. 96.
    Campisi R, Nathan L, Pampaloni MH, et al.: Noninvasive assessment of coronary microcirculatory function in postmenopausal women and effects of short-term and long-term estrogen administration. Circulation 2002, 105:425–430.PubMedCrossRefGoogle Scholar
  97. 97.
    Herrington DM, Reboussin DM, Brosnihan KB, et al.: Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000, 343:522–529.PubMedCrossRefGoogle Scholar
  98. 98.
    Hulley S, Grady D, Bush T, et al.: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/ progestin Replacement Study (HERS) Research Group. JAMA 1998, 280:605–613.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2005

Authors and Affiliations

  • Alessia Fornoni
    • 1
  • Leopoldo Raij
    • 1
  1. 1.Division of Nephrology and HypertensionUniversity of Miami School of Medicine and Veterans Affairs Medical CenterMiamiUSA

Personalised recommendations