Current Hypertension Reports

, Volume 10, Issue 6, pp 434–439 | Cite as

Leptin and mechanisms of endothelial dysfunction and cardiovascular disease

  • Jarrod D. Knudson
  • Gregory A. Payne
  • Léna Borbouse
  • Johnathan D. Tune


Leptin, a product of the obesity gene, is a molecule that has received much attention since its cloning in 1994. Initially, most work centered around the effects of leptin on satiety and energy balance. However, in recent years there has been an intense focus on leptin as it relates to the cardiovascular system. Plasma leptin concentration is markedly elevated in obesity and the metabolic syndrome, both of which are associated with increased incidence of cardiovascular pathologies. In many studies, hyperleptinemia has been linked to endothelial dysfunction (a known precursor to atherosclerotic cardiovascular disease) and activation of the sympathetic nervous system. Additionally, recent evidence suggests that leptin released from perivascular adipose tissue may also have deleterious effects on the underlying vasculature, including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, leptin-mediated sympathetic activation, and leptin as a significant perivascular adipose-derived factor.


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References and Recommended Reading

  1. 1.
    Zhang Y, Proenca R, Maffei M, et al.: Positional cloning of the mouse obese gene and its human homologue. Nature 1994, 372:425–432.PubMedCrossRefGoogle Scholar
  2. 2.
    Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature 1998, 395:763–770.PubMedCrossRefGoogle Scholar
  3. 3.
    Pelleymounter MA, Cullen MJ, Baker MB, et al.: Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995, 269:540–543.PubMedCrossRefGoogle Scholar
  4. 4.
    Montague CT, Farooqi IS, Whitehead JP, et al.: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997, 387:903–908.PubMedCrossRefGoogle Scholar
  5. 5.
    Masuzaki H, Ogawa Y, Isse N, et al.: Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose tissue. Diabetes 1995, 44:855–858.PubMedCrossRefGoogle Scholar
  6. 6.
    Bajnok L, Seres I, Varga Z, et al.: Relationship of endogenous hyperleptinemia to serum paraoxonase 1, cholesteryl ester transfer protein, and lecithin cholesterol acyltransferase in obese individuals. Metabolism 2007, 56:1542–1549.PubMedCrossRefGoogle Scholar
  7. 7.
    Ramos AP, de Abreu MR, Vendramini RC, et al.: Decrease in circulating glucose, insulin and leptin levels and improvement in insulin resistance at 1 and 3 months after gastric bypass. Obes Surg 2006, 16:1359–1364.PubMedCrossRefGoogle Scholar
  8. 8.
    Jequier E: Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci 2002, 967:379–388.PubMedCrossRefGoogle Scholar
  9. 9.
    Ozata M, Ozdemir IC, Licinio J: Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 1999, 84:3686–3695.PubMedCrossRefGoogle Scholar
  10. 10.
    Soderberg S, Ahren B, Jansson JH, et al.: Leptin is associated with increased risk of myocardial infarction. J Intern Med 1999, 246:409–418.PubMedCrossRefGoogle Scholar
  11. 11.
    Wallace AM, McMahon AD, Packard CJ, et al.: Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation 2001, 104:3052–3056.PubMedCrossRefGoogle Scholar
  12. 12.
    Knudson JD, Dincer UD, Zhang C, et al.: Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction. Am J Physiol Heart Circ Physiol 2005, 289:H48–H56.PubMedCrossRefGoogle Scholar
  13. 13.
    Ross R, Faggiotto A, Bowen-Pope D, Raines E: The role of endothelial injury and platelet and macrophage interactions in atherosclerosis. Circulation 1984, 70:III77–III82.PubMedGoogle Scholar
  14. 14.
    Thakali KM, Lau Y, Fink GD, et al.: Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function. J Cardiovasc Pharmacol 2006, 47:742–750.PubMedCrossRefGoogle Scholar
  15. 15.
    Cardillo C, Campia U, Iantorno M, Panza JA: Enhanced vascular activity of endogenous endothelin-1 in obese hypertensive patients. Hypertension 2004, 43:36–40.PubMedCrossRefGoogle Scholar
  16. 16.
    Loffreda S, Yang SQ, Lin HZ, et al.: Leptin regulates proinflammatory immune responses. FASEB J 1998, 12:57–65.PubMedGoogle Scholar
  17. 17.
    Shamsuzzaman AS, Winnicki M, Wolk R, et al.: Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation 2004, 109:2181–2185.PubMedCrossRefGoogle Scholar
  18. 18.
    Pasceri V, Willerson JT, Yeh ET: Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000, 102:2165–2168.PubMedGoogle Scholar
  19. 19.
    Schafer K, Halle M, Goeschen C, et al.: Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol 2004, 24:112–117.PubMedCrossRefGoogle Scholar
  20. 20.
    Yamagishi SI, Edelstein D, Du XL, et al.: Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 2001, 276:25096–25100.PubMedCrossRefGoogle Scholar
  21. 21.
    Galili O, Versari D, Sattler KJ, et al.: Early experimental obesity is associated with coronary endothelial dysfunction and oxidative stress. Am J Physiol Heart Circ Physiol 2007, 292:H904–H911.PubMedCrossRefGoogle Scholar
  22. 22.
    Beltowski J, Wojcicka G, Marciniak A, Jamroz A: Oxidative stress, nitric oxide production, and renal sodium handling in leptin-induced hypertension. Life Sci 2004, 74:2987–3000.PubMedCrossRefGoogle Scholar
  23. 23.
    Lembo G, Vecchione C, Fratta L, et al.: Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes 2000, 49:293–297.PubMedCrossRefGoogle Scholar
  24. 24.
    Kimura K, Tsuda K, Baba A, et al.: Involvement of nitric oxide in endothelium-dependent arterial relaxation by leptin. Biochem Biophys Res Commun 2000, 273:745–749.PubMedCrossRefGoogle Scholar
  25. 25.
    Vecchione C, Aretini A, Maffei A, et al.: Cooperation between insulin and leptin in the modulation of vascular tone. Hypertension 2003, 42:166–170.PubMedCrossRefGoogle Scholar
  26. 26.
    Kim JA, Montagnani M, Koh KK, Quon MJ: Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006, 113:1888–1904.PubMedCrossRefGoogle Scholar
  27. 27.
    Yanai H, Tomono Y, Ito K, et al.: The underlying mechanisms for development of hypertension in the metabolic syndrome. Nutr J 2008, 7:10.PubMedCrossRefGoogle Scholar
  28. 28.
    Julius S, Jamerson K: Sympathetics, insulin resistance and coronary risk in hypertension: the ‘chicken-and-egg’ question. J Hypertens 1994, 12:495–502.PubMedCrossRefGoogle Scholar
  29. 29.
    Rahmouni K, Haynes WG: Leptin and the cardiovascular system. Recent Prog Horm Res 2004, 59:225–244.PubMedCrossRefGoogle Scholar
  30. 30.
    Carlyle M, Jones OB, Kuo JJ, Hall JE: Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension 2002, 39:496–501.PubMedCrossRefGoogle Scholar
  31. 31.
    Haynes WG, Morgan DA, Walsh SA, et al.: Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 1997, 100:270–278.PubMedCrossRefGoogle Scholar
  32. 32.
    Correia ML, Haynes WG: Leptin, obesity and cardiovascular disease. Curr Opin Nephrol Hypertens 2004, 13:215–223.PubMedCrossRefGoogle Scholar
  33. 33.
    Kuo JJ, Jones OB, Hall JE: Chronic cardiovascular and renal actions of leptin during hyperinsulinemia. Am J Physiol Regul Integr Comp Physiol 2003, 284:R1037–R1042.PubMedGoogle Scholar
  34. 34.
    Masuo K, Mikami H, Ogihara T, Tuck ML: Weight gain-induced blood pressure elevation. Hypertension 2000, 35:1135–1140.PubMedGoogle Scholar
  35. 35.
    Cassis LA, English VL, Bharadwaj K, Boustany CM: Differential effects of local versus systemic angiotensin II in the regulation of leptin release from adipocytes. Endocrinology 2004, 145:169–174.PubMedCrossRefGoogle Scholar
  36. 36.
    Sharma AM, Engeli S, Pischon T: New developments in mechanisms of obesity-induced hypertension: role of adipose tissue. Curr Hypertens Rep 2001, 3:152–156.PubMedCrossRefGoogle Scholar
  37. 37.
    Fortuno A, Rodriguez A, Gomez-Ambrosi J, et al.: Leptin inhibits angiotensin II-induced intracellular calcium increase and vasoconstriction in the rat aorta. Endocrinology 2002, 143:3555–3560.PubMedCrossRefGoogle Scholar
  38. 38.
    Kassab S, Kato T, Wilkins FC, et al.: Renal denervation attenuates the sodium retention and hypertension associated with obesity. Hypertension 1995, 25:893–897.PubMedGoogle Scholar
  39. 39.
    Hall JE, Hildebrandt DA, Kuo J: Obesity hypertension: role of leptin and sympathetic nervous system. Am J Hypertens 2001, 14:103S–115S.PubMedCrossRefGoogle Scholar
  40. 40.
    Eringa EC, Bakker W, Smulders YM, et al.: Regulation of vascular function and insulin sensitivity by adipose tissue: focus on perivascular adipose tissue. Microcirculation 2007, 14:389–402.PubMedCrossRefGoogle Scholar
  41. 41.
    Gao YJ, Lu C, Su LY, et al.: Modulation of vascular function by perivascular adipose tissue: the role of endothelium and hydrogen peroxide. Br J Pharmacol 2007, 151:323–331.PubMedCrossRefGoogle Scholar
  42. 42.
    Gálvez B, de Castro J, Herold D, et al.: Perivascular adipose tissue and mesenteric vascular function in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 2006, 26:1297–1302.PubMedCrossRefGoogle Scholar
  43. 43.
    Gao YJ, Zeng ZH, Teoh K, et al.: Perivascular adipose tissue modulates vascular function in the human internal thoracic artery. J Thorac Cardiovasc Surg 2005, 130:1130–1136.PubMedCrossRefGoogle Scholar
  44. 44.
    Dubrovska G, Verlohren S, Luft FC, Gollasch M: Mechanisms of ADRF release from rat aortic adventitial adipose tissue. Am J Physiol Heart Circ Physiol 2004, 286:H1107–H1113.PubMedCrossRefGoogle Scholar
  45. 45.
    Payne GA, Borbouse L, Bratz IN, et al.: Endogenous adipose-derived factors diminish coronary endothelial function via inhibition of nitric oxide synthase. Microcirculation 2008, 15:417–426.PubMedCrossRefGoogle Scholar
  46. 46.
    Reifenberger MS, Turk JR, Newcomer SC, et al.: Perivascular fat alters reactivity of coronary artery: effects of diet and exercise. Med Sci Sports Exerc 2007, 39:2125–2134.PubMedCrossRefGoogle Scholar
  47. 47.
    Cheng KH, Chu CS, Lee KT, et al.: Adipocytokines and proinflammatory mediators from abdominal and epicardial adipose tissue in patients with coronary artery disease. Int J Obes (Lond) 2008, 32:268–274.CrossRefGoogle Scholar
  48. 48.
    Guzik TJ, Hoch NE, Brown KA, et al.: Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007, 204:2449–2460.PubMedCrossRefGoogle Scholar
  49. 49.
    Henrichot E, Juge-Aubry CE, Pernin A, et al.: Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis? Arterioscler Thromb Vasc Biol 2005, 25:2594–2599.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  • Jarrod D. Knudson
    • 1
  • Gregory A. Payne
  • Léna Borbouse
  • Johnathan D. Tune
  1. 1.Department of PediatricsBaylor College of MedicineHoustonUSA

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