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Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK–eNOS Pathway

International Journal of Obesity volume 34, pages 165–171 (2010)Cite this article

Abstract

Objective:

Hypoadiponectinemia has been proved to be closely related to endothelial dysfunction in peripheral arteries and is thought to be an independent risk factor for cardiovascular disease. The objective of this study was to investigate whether adiponectin might independently improve endothelial dysfunction in aorta isolated from high-fat-diet-induced obese. Sprague-Dawley rat and to study the mechanism involved.

Research Design and Subjects:

Male Sprague-Dawley rats were fed with a regular or a high-fat diet for 6 weeks. The aorta was isolated, and vascular segments were incubated with vehicle or the globular adiponectin (globular domain (gAD); 2 mg ml−1) for 2 h. The effect of gAD on endothelial function and nitric oxide (NO) production was determined. Human aortic endothelial cells in primary culture were treated with vehicle or gAD (4 mg ml−1). The effect of gAD on the level of phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177, AMPK at Thr176 and Akt at Ser473 in endothelial cells were determined.

Results:

Severe endothelial dysfunction was observed in high-fat diet fed rat aortic segments. After gAd incubation, the endothelium-dependent relaxation was partly improved and total production of nitric oxide as result of enhanced eNOS activity was also increased. In the cultured endothelial cell line HUVEC, globular adiponectin increased the activity of eNOS through activating AMPK by stimulating its phosphorylation at Thr176 but not Akt.

Conclusion:

The demonstration in the current study that adiponectin reverses endothelial dysfunction through increasing NO production by eNOS phosphorylation, and decreasing NO inactivation by blocking superoxide production provides a new direction in the prevention of vascular injury in the obesity population.

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References

  1. Ross R . The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801–809.

    Article  CAS  Google Scholar 

  2. Bonetti PO, Lerman LO, Lerman A . Endothelial dysfunction—A marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003; 23: 168–175.

    Article  CAS  Google Scholar 

  3. Pierce GL, Beske SD, Lawson BR, Southall KL, Benay FJ, Donato AJ et al. Weight loss alone improves conduit and resistance artery endothelial function in young and older overweight/obese adults. Hypertension 2008; 52: 72–79.

    Article  CAS  Google Scholar 

  4. Burke GL, Bertoni AG, Shea S, Tracy R, Watson KE, Blumenthal RS et al. The impact of obesity on cardiovascular disease risk factors and subclinical vascular disease: the Multi-Ethnic Study of Atherosclerosis. Arch Intern Med 2008; 168: 928–935.

    Article  Google Scholar 

  5. Al Suwaidi J, Higano ST, Holmes Jr DR, 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: 1523–152.

    Article  CAS  Google Scholar 

  6. Kawashima S, Yokoyama M . Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24: 998–1005.

    Article  CAS  Google Scholar 

  7. Lavi S, Yang EH, Prasad A, Mathew V, Barsness GW, Rihal CS et al. The interaction between coronary endothelial dysfunction, local oxidative stress, and endogenous nitric oxide in humans. Hypertension 2008; 51: 127–133.

    Article  CAS  Google Scholar 

  8. Touyz RM, Schiffrin EL . Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 2004; 122: 339–352.

    Article  CAS  Google Scholar 

  9. Okui H, Hamasaki S, Ishida S, Kataoka T, Orihara K, Fukudome T et al. Adiponectin is a better predictor of endothelial function of the coronary artery than HOMA-R, body mass index, immunoreactive insulin, or triglycerides. Int J Cardiol 2008; 126: 53–61.

    Article  Google Scholar 

  10. Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N, Tagawa T et al. Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 2003; 88: 3236–3240.

    Article  CAS  Google Scholar 

  11. Chow WS, Cheung BMY, Tso AWK, Xu AM, Wat NMS, Fong CHY et al. Hypoadiponectinemia as a predictor for the development of hypertension—A 5-year prospective study. Hypertension 2007; 49: 1455–1461.

    Article  CAS  Google Scholar 

  12. Koenig W, Khuseyinova N, Baumert J, Meisinger C, Lowel H . Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany. J Am Coll Cardiol 2006; 48: 1369–1377.

    Article  CAS  Google Scholar 

  13. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 2003; 23: 85–89.

    Article  CAS  Google Scholar 

  14. Everett SA, Dennis MF, Tozer GM, Prise VE, Wardman P, Stratford MRL . Nitric-oxide in biological-fluids—analysis of nitrite and nitrate by high-performance ion chromatography. In: Heftmann E (ed). 7th International Ion Chromatography Symposium (IICS 94). Elsevier Science BV: Turin, Italy, 1994. pp 437–442.

    Google Scholar 

  15. Calles-Escandon J, Cipolla M . Diabetes and endothelial dysfunction: a clinical perspective. Endocr Rev 2001; 22: 36–52.

    Article  CAS  Google Scholar 

  16. Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H et al. Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 2003; 42: 231–234.

    Article  CAS  Google Scholar 

  17. Ouedraogo R, Gong Y, Berzins B, Wu X, Mahadev K, Hough K et al. Adiponectin deficiency increases leukocyte–endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest 2007; 117: 1718–1726.

    Article  CAS  Google Scholar 

  18. Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A et al. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 2006; 47: 1108–1116.

    Article  CAS  Google Scholar 

  19. Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ . Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 2003; 278: 45021–45026.

    Article  CAS  Google Scholar 

  20. Hattori Y, Suzuki M, Hattori S, Kasai K . Globular adiponectin upregulates nitric oxide production in vascular endothelial cells. Diabetologia 2003; 46: 1543–1549.

    Article  CAS  Google Scholar 

  21. Xi W, Satoh H, Kase H, Suzuki K, Hattori Y . Stimulated HSP90 binding to eNOS and activation of the PI3–Akt pathway contribute to globular adiponectin-induced NO production: vasorelaxation in response to globular adiponectin. Biochem Biophys Res Commun 2005; 332: 200–205.

    Article  CAS  Google Scholar 

  22. Motoshima H, Wu X, Mahadev K, Goldstein BJ . Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL. Biochem Biophys Res Commun 2004; 315: 264–271.

    Article  CAS  Google Scholar 

  23. Ouedraogo R, Wu X, Xu SQ, Fuchsel L, Motoshima H, Mahadev K et al. Adiponectin suppression of high glucose-induced reactive oxygen species in vascular endothelial cells: evidence for involvement of a cAMP signaling pathway. Diabetes 2006; 55: 1840–1846.

    Article  CAS  Google Scholar 

  24. Cao Y, Tao L, Yuan Y, Jiao X, Lau WB, Wang Y et al. Endothelial dysfunction in adiponectin deficiency and its mechanisms involved. J Mol Cell Cardiol 2009; 46: 413–419.

    Article  CAS  Google Scholar 

  25. Davis BJ, Xie Z, Viollet B, Zou MH . Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 2006; 55: 496–505.

    Article  CAS  Google Scholar 

  26. Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T et al. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem 2004; 279: 1304–1309.

    Article  CAS  Google Scholar 

  27. Brook RD, Bard RL, Rubenfire M, Ridker PM, 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.

    Article  CAS  Google Scholar 

  28. Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem 2003; 278: 2461–2468.

    Article  CAS  Google Scholar 

  29. Montagnani M, Chen H, Barr VA, Quon MJ . Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem 2001; 276: 30392–30398.

    Article  CAS  Google Scholar 

  30. Wu XD, Motoshima H, Mahadev K, Stalker TJ, Scalia R, Goldstein BJ . Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes 2003; 52: 1355–1363.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by grants from National Natural Science Foundation of China (No. 30570874 and No. 30370679).

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China

    G Deng, Y-R Yu & M-R Li

  2. Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu City, Sichuan Province, China

    Y Long

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Correspondence to Y-R Yu.

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Deng, G., Long, Y., Yu, YR. et al. Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK–eNOS Pathway. Int J Obes 34, 165–171 (2010). https://doi.org/10.1038/ijo.2009.205

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