Obesity and Endothelial Dysfunction

ABSTRACT

Obesity is becoming more prevalent in the developed world because of the abundance of food and the decrease of physical activity. Obesity is a risk factor for a host of diseases from arthritis to cardiovascular disease. The precise mechanisms by which obesity promotes cardiovascular disease are not well understood but are likely to include metabolic and inflammatory responses to the increased amount of stored fat. The endothelium plays a pivotal role in maintaining vascular health. Impaired endothelial function is an independent predictor of cardiovascular disease. Most studies of vascular function in obese subjects have demonstrated impaired endothelial function. This impairment of endothelial function becomes obvious early on, long before any vascular abnormalities become clinically relevant and detectable. Better understanding of the mediators of obesity-induced endothelial dysfunction may lead to the identification of new targets for interventions that may prevent or postpone the development of obesity-related cardiovascular disease.

Obesity - endothelium - nitric oxide - free fatty acids - endothelial activation - serum markers

REFERENCES

• 1 Flegal K M, Carroll M D, Kuczmarski R J, Johnson C L. Overweight and obesity in the United States: prevalence and trends, 1960-1994.  Int J Obes Relat Metab Disord. 1998;  22 39-47
• 2 Flegal K M, Carroll M D, Ogden C L, Johnson C L. Prevalence and trends in obesity among US adults, 1999-2000.  JAMA. 2002;  288 1723-1727
• 3 Luo J, Hu F B. Time trends of obesity in pre-school children in China from 1989 to 1997.  Int J Obes Relat Metab Disord. 2002;  26 553-558
• 4 Mokdad A H, Marks J S, Stroup D F, Gerberding J L. Actual causes of death in the United States, 2000.  JAMA. 2004;  291 1238-1245
• 5 Ninomiya J K, L'Italien G, Criqui M H, Whyte J L, Gamst A, Chen R S. Association of the metabolic syndrome with history of myocardial infarction and stroke in the third national health and nutrition examination survey.  Circulation. 2004;  109 42-46
• 6 Steinberg H O, Chaker H, Leaming R, Johnson A, Brechtel G, Baron A D. Obesity/Insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.  J Clin Invest. 1996;  97 2601-2610
• 7 Perticone F, Ceravolo R, Candigliota M et al.. Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C.  Diabetes. 2001;  50 159-165
• 8 Rosito G A, D'Agostino R B, Massaro J et al.. Association between obesity and a prothrombotic state: the Framingham Offspring Study.  Thromb Haemost. 2004;  91 683-689
• 9 Ferri C, Bellini C, Desideri G et al.. Circulating endothelin-1 levels in obese patients with the metabolic syndrome.  Exp Clin Endocrinol Diabetes. 1997;  105 38-40
• 10 Mather K J, Mirzamohammadi B, Lteif A, Steinberg H O, Baron A D. Endothelin contributes to basal vascular tone and endothelial dysfunction in human obesity and type 2 diabetes.  Diabetes. 2002;  51 3517-3523
• 11 Escobar-Morreale H F, Villuendas G, Botella-Carretero J I, Sancho J, San Millan J L. Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women.  Diabetologia. 2003;  46 625-633
• 12 Steinberg H O, Paradisi G, Hook G, Crowder K, Cronin J, Baron A D. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production.  Diabetes. 2000;  49 1231-1238
• 13 Stuhlinger M C, Abbasi F, Chu J W et al.. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.  JAMA. 2002;  287 1420-1426
• 14 Furchgott R F, Zawadzki J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.  Nature. 1980;  288 373-382
• 15 Steinberg H O, Baron A D. Insulin-mediated vasodilation: why one's physiology could be the other’s pharmacology.  Diabetologia. 1999;  42 493-495
• 16 Serne E H, Stehouwer C D, ter Maaten J C et al.. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects.  Circulation. 1999;  99 896-902
• 17 Bhagat K, Hingorani A, Vallance P. Flow associated or flow mediated dilatation? More than just semantics.  Heart. 1997;  78 7-8
• 18 Lonn E, Yan R, Anderson T et al.. Obesity predicts atherogenic abnormalities and atherosclerosis.  Circulation. 2003;  108 IV-743
• 19 De Roos N M, Bots M L, Schouten E G, Katan M B. Within-subject variability of flow-mediated vasodilation of the brachial artery in healthy men and women: implications for experimental studies.  Ultrasound Med Biol. 2003;  29 401-406
• 20 Kaku B, Mizuno S, Ohsato K et al.. The correlation between coronary stenosis index and flow-mediated dilation of the brachial artery.  Jpn Circ J. 1998;  62 425-430
• 21 Gokce N, Keaney Jr J F, Hunter L M et al.. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease.  J Am Coll Cardiol. 2003;  41 1769-1775
• 22 Vigili de Kreutzenberg S, Kiwanuka E, Tiengo A, Avogaro A. Visceral obesity is characterized by impaired nitric oxide-independent vasodilation.  Eur Heart J. 2003;  24 1210-1215
• 23 Steinberg H O, Paradisi G, Cronin J et al.. Type II diabetes abrogates sex differences in endothelial function in premenopausal women.  Circulation. 2000;  101 2040-2046
• 24 Hashimoto M, Akishita M, Eto M et al.. The impairment of flow-mediated vasodilatation in obese men with visceral fat accumulation.  Int J Obes Relat Metab Disord. 1998;  22 477-484
• 25 Brook R D, Bard R L, Rubenfire M, Ridker P M, Rajagopalan S. Usefulness of visceral obesity (waist/hip ratio) in predicting vascular endothelial function in healthy overweight adults.  Am J Cardiol. 2001;  88 1264-1269
• 26 Aggoun Y, Tounian P, Dabbas-Tyan M et al.. Arterial rigidity and endothelial dysfunction in obese children.  Arch Mal Coeur Vaiss. 2002;  95 631-635
• 27 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
• 28 Petrie J R, Stehouwer C D. Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease.  Circulation. 1996;  93 1331-1333
• 29 Laakso M, Edelman S V, Brechtel G, Baron A D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese men.  J Clin Invest. 1990;  85 1844-1852
• 30 Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin's vascular effects in humans.  J Clin Invest. 1994;  94 2511-2515
• 31 Steinberg H O, Brechtel G, Johnson A, Fineberg N, Baron A D. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent.  J Clin Invest. 1994;  94 1172-1179
• 32 Laakso M, Edelman S V, Brechtel G, Baron A D. Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM.  Diabetes. 1992;  41 1076-1083
• 33 Vollenweider P, Randin D, Tappy L, Jequier E, Nicod P, Scherrer U. Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans.  J Clin Invest. 1994;  93 2365-2371
• 34 Yki-Jarvinen H, Young A A, Lamkin C, Foley J E. Kinetics of glucose disposal in whole body and across the forearm in man.  J Clin Invest. 1987;  79 1713-1719
• 35 Yki-Jarvinen H, Utriainen T. Insulin-induced vasodilatation: physiology or pharmacology?.  Diabetologia. 1998;  41 369-379
• 36 Laine H, Knuuti M J, Ruotsalainen U et al.. Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle.  J Hypertens. 1998;  16 211-219
• 37 Tack C J, Ong M K, Lutterman J A, Smits P. Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone.  Diabetologia. 1998;  41 569-576
• 38 Al Suwaidi J, Higano S T, Holmes Jr D R, Lennon R, Lerman A. Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries.  J Am Coll Cardiol. 2001;  37 1523-1528
• 39 Sundell J, Laine H, Luotolahti M et al.. Obesity affects myocardial vasoreactivity and coronary flow response to insulin.  Obes Res. 2002;  10 617-624
• 40 Shimabukuro M, Shinzato T, Higa S et al.. Enhanced insulin response relates to acetylcholine-induced vasoconstriction in vasospastic angina.  J Am Coll Cardiol. 1995;  25 356-361
• 41 Ferri C, Desideri G, Valenti M et al.. Early upregulation of endothelial adhesion molecules in obese hypertensive men.  Hypertension. 1999;  34 568-573
• 42 Bagg W, Ferri C, Desideri G, Gamble G, Ockelford P, Braatvedt G D. The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes.  J Clin Endocrinol Metab. 2001;  86 5491-5497
• 43 Ito H, Ohshima A, Inoue M et al.. Weight reduction decreases soluble cellular adhesion molecules in obese women.  Clin Exp Pharmacol Physiol. 2002;  29 399-404
• 44 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
• 45 Straczkowski M, Lewczuk P, Dzienis-Straczkowska S, Kowalska I, Stepien A, Kinalska I. Elevated soluble intercellular adhesion molecule-1 levels in obesity: relationship to insulin resistance and tumor necrosis factor-alpha system activity.  Metabolism. 2002;  51 75-78
• 46 Leinonen E, Hurt-Camejo E, Wiklund O, Hulten L M, Hiukka A, Taskinen M R. Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes.  Atherosclerosis. 2003;  166 387-394
• 47 Baron A D. Hemodynamic actions of insulin.  Am J Physiol. 1994;  267 E187-E202
• 48 Baron A D, Tarshoby M, Hook G et al.. Interaction between insulin sensitivity and muscle perfusion on glucose uptake in human skeletal muscle: evidence for capillary recruitment.  Diabetes. 2000;  49 768-774
• 49 Steinberg H O, Paradisi G, Hook G, Crowder K, Cronin J, Baron A D. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production.  Diabetes. 2000;  49 1231-1238
• 50 Dresner A, Laurent D, Marcucci M et al.. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.  J Clin Invest. 1999;  103 253-259
• 51 Lundman P, Eriksson M J, Stuhlinger M, Cooke J P, Hamsten A, Tornvall P. Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine.  J Am Coll Cardiol. 2001;  38 111-116
• 52 Esposito K, Pontillo A, Di Palo C et al.. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial.  JAMA. 2003;  289 1799-1804
• 53 Oflaz H, Ozbey N, Mantar F et al.. Determination of endothelial function and early atherosclerotic changes in healthy obese women.  Diabetes Nutr Metab. 2003;  16 176-181
• 54 Suwaidi J A, Hamasaki S, Higano S T, Nishimura R A, Holmes Jr D R, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.  Circulation. 2000;  101 948-954