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Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2–dependent mechanisms

Nature Medicine volume 11, pages 1096–1103 (2005)Cite this article

Abstract

Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-α expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-α production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-α production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-α production. Adiponectin induced cyclooxygenase (COX)-2–dependent synthesis of prostaglandin E2 in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-α production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2–dependent mechanisms.

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Figure 1: Increased myocardial infarction, myocardial apoptosis and TNF-α expression in APN-KO mice subjected to ischemia-reperfusion injury.
Figure 2: Adenovirus-mediated expression of adiponectin diminishes infarct size, apoptosis and TNF-α production after ischemia-reperfusion in wild-type (WT) and APN-KO mice.
Figure 3: AMPK-dependent inhibition of cardiac myocyte and fibroblast apoptosis by adiponectin.
Figure 4: Adiponectin suppresses LPS-induced secretion of TNF-α from neonatal myocytes through a COX-2–dependent pathway.
Figure 5: Inhibition of COX-2 partially prevents the protective actions of adiponectin on myocardial infarct size after ischemia-reperfusion injury in wild-type (WT) and APN-KO mice.

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References

  1. Eisenberg, M.S. & Mengert, T.J. Cardiac resuscitation. N. Engl. J. Med. 344, 1304–1313 (2001).

    Article  CAS  Google Scholar 

  2. Rogers, W.J. et al. Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3. J. Am. Coll. Cardiol. 36, 2056–2063 (2000).

    Article  CAS  Google Scholar 

  3. Wolk, R., Berger, P., Lennon, R.J., Brilakis, E.S. & Somers, V.K. Body mass index: a risk factor for unstable angina and myocardial infarction in patients with angiographically confirmed coronary artery disease. Circulation 108, 2206–2211 (2003).

    Article  Google Scholar 

  4. Orlander, P.R. et al. The relation of diabetes to the severity of acute myocardial infarction and post-myocardial infarction survival in Mexican-Americans and non-Hispanic whites. The Corpus Christi Heart Project. Diabetes 43, 897–902 (1994).

    Article  CAS  Google Scholar 

  5. Scherer, P.E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H.F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).

    Article  CAS  Google Scholar 

  6. Hu, E., Liang, P. & Spiegelman, B.M. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 271, 10697–10703 (1996).

    Article  CAS  Google Scholar 

  7. Maeda, K. et al. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem. Biophys. Res. Commun. 221, 286–289 (1996).

    Article  CAS  Google Scholar 

  8. Arita, Y. et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 79–83 (1999).

    Article  CAS  Google Scholar 

  9. Ouchi, N. et al. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 107, 671–674 (2003).

    Article  CAS  Google Scholar 

  10. Ouchi, N., Kihara, S., Funahashi, T., Matsuzawa, Y. & Walsh, K. Obesity, adiponectin and vascular inflammatory disease. Curr. Opin. Lipidol. 14, 561–566 (2003).

    Article  CAS  Google Scholar 

  11. Hotta, K. et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler. Thromb. Vasc. Biol. 20, 1595–1599 (2000).

    Article  CAS  Google Scholar 

  12. Iwashima, Y. et al. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension 43, 1318–1323 (2004).

    Article  CAS  Google Scholar 

  13. Kumada, M. et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler. Thromb. Vasc. Biol. 23, 85–89 (2003).

    Article  CAS  Google Scholar 

  14. Maeda, N. et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat. Med. 8, 731–737 (2002).

    Article  CAS  Google Scholar 

  15. Shibata, R. et al. Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of amp-activated protein kinase signaling. J. Biol. Chem. 279, 28670–28674 (2004).

    Article  CAS  Google Scholar 

  16. Shibata, R. et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat. Med. 10, 1384–1389 (2004).

    Article  CAS  Google Scholar 

  17. Pischon, T. et al. Plasma adiponectin levels and risk of myocardial infarction in men. J. Am. Med. Assoc. 291, 1730–1737 (2004).

    Article  CAS  Google Scholar 

  18. Kojima, S. et al. The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction. Heart 89, 667 (2003).

    Article  CAS  Google Scholar 

  19. Russell, R.R. III et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J. Clin. Invest. 114, 495–503 (2004).

    Article  CAS  Google Scholar 

  20. Ouchi, N. et al. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J. Biol. Chem. 279, 1304–1309 (2004).

    Article  CAS  Google Scholar 

  21. Frangogiannis, N.G., Smith, C.W. & Entman, M.L. The inflammatory response in myocardial infarction. Cardiovasc. Res. 53, 31–47 (2002).

    Article  CAS  Google Scholar 

  22. Wagner, D.R. et al. Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor necrosis factor-alpha. Circ. Res. 82, 47–56 (1998).

    Article  CAS  Google Scholar 

  23. Meja, K.K., Barnes, P.J. & Giembycz, M.A. Characterization of the prostanoid receptor(s) on human blood monocytes at which prostaglandin E2 inhibits lipopolysaccharide-induced tumour necrosis factor-alpha generation. Br. J. Pharmacol. 122, 149–157 (1997).

    Article  CAS  Google Scholar 

  24. Pruimboom, W.M. et al. Interactions between cytokines and eicosanoids: a study using human peritoneal macrophages. Immunol. Lett. 41, 255–260 (1994).

    Article  CAS  Google Scholar 

  25. Eliopoulos, A.G., Dumitru, C.D., Wang, C.C., Cho, J. & Tsichlis, P.N. Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J. 21, 4831–4840 (2002).

    Article  CAS  Google Scholar 

  26. Xiao, C.Y. et al. Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4. Circulation 109, 2462–2468 (2004).

    Article  CAS  Google Scholar 

  27. Parsa, C.J. et al. Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts. J. Biol. Chem. 279, 20655–20662 (2004).

    Article  CAS  Google Scholar 

  28. Kobayashi, H. et al. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ. Res. 94, e27–e31 (2004).

    Article  CAS  Google Scholar 

  29. Russell, R.R. III, Bergeron, R., Shulman, G.I. & Young, L.H. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am. J. Physiol. 277, H643–H649 (1999).

    CAS  PubMed  Google Scholar 

  30. Frangogiannis, N.G. et al. Resident cardiac mast cells degranulate and release preformed TNF-alpha, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion. Circulation 98, 699–710 (1998).

    Article  CAS  Google Scholar 

  31. Kupatt, C. et al. Tumor necrosis factor-alpha contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts. Circ. Res. 84, 392–400 (1999).

    Article  CAS  Google Scholar 

  32. Maekawa, N. et al. Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-alpha. J. Am. Coll. Cardiol. 39, 1229–1235 (2002).

    Article  CAS  Google Scholar 

  33. Gurevitch, J. et al. Anti-tumor necrosis factor-alpha improves myocardial recovery after ischemia and reperfusion. J. Am. Coll. Cardiol. 30, 1554–1561 (1997).

    Article  CAS  Google Scholar 

  34. Bolli, R. et al. Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc. Res. 55, 506–519 (2002).

    Article  CAS  Google Scholar 

  35. Camitta, M.G. et al. Cyclooxygenase-1 and -2 knockout mice demonstrate increased cardiac ischemia/reperfusion injury but are protected by acute preconditioning. Circulation 104, 2453–2458 (2001).

    Article  CAS  Google Scholar 

  36. Adderley, S.R. & Fitzgerald, D.J. Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. J. Biol. Chem. 274, 5038–5046 (1999).

    Article  CAS  Google Scholar 

  37. Hohlfeld, T., Meyer-Kirchrath, J., Vogel, Y.C. & Schror, K. Reduction of infarct size by selective stimulation of prostaglandin EP(3)receptors in the reperfused ischemic pig heart. J. Mol. Cell. Cardiol. 32, 285–296 (2000).

    Article  CAS  Google Scholar 

  38. Xiao, C.Y. et al. Roles of prostaglandin I(2) and thromboxane A(2) in cardiac ischemia-reperfusion injury: a study using mice lacking their respective receptors. Circulation 104, 2210–2215 (2001).

    Article  CAS  Google Scholar 

  39. Bryant, D. et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 97, 1375–1381 (1998).

    Article  CAS  Google Scholar 

  40. Sugano, M. et al. Local delivery of soluble TNF-alpha receptor 1 gene reduces infarct size following ischemia/reperfusion injury in rats. Mol. Cell. Biochem. 266, 127–132 (2004).

    Article  CAS  Google Scholar 

  41. Li, Q. et al. Gene therapy with inducible nitric oxide synthase protects against myocardial infarction via a cyclooxygenase-2-dependent mechanism. Circ. Res. 92, 741–748 (2003).

    Article  CAS  Google Scholar 

  42. Arnaud, C., Joyeux-Faure, M., Godin-Ribuot, D. & Ribuot, C. COX-2: an in vivo evidence of its participation in heat stress-induced myocardial preconditioning. Cardiovasc. Res. 58, 582–588 (2003).

    Article  CAS  Google Scholar 

  43. Solomon, S.D. et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352, 1071–1080 (2005).

    Article  CAS  Google Scholar 

  44. Bresalier, R.S. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352, 1092–1102 (2005).

    Article  CAS  Google Scholar 

  45. Fitzgerald, G.A. Coxibs and cardiovascular disease. N. Engl. J. Med. 351, 1709–1711 (2004).

    Article  CAS  Google Scholar 

  46. Fruebis, J. et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc. Natl. Acad. Sci. USA 98, 2005–2010 (2001).

    Article  CAS  Google Scholar 

  47. Berg, A.H., Combs, T.P., Du, X., Brownlee, M. & Scherer, P.E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7, 947–953 (2001).

    Article  CAS  Google Scholar 

  48. Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295 (2002).

    Article  CAS  Google Scholar 

  49. Nagata, D., Mogi, M. & Walsh, K. AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J. Biol. Chem. 278, 31000–31006 (2003).

    Article  CAS  Google Scholar 

  50. Fujio, Y., Nguyen, T., Wencker, D., Kitsis, R.N. & Walsh, K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation 101, 660–667 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants HL66957, HL77774, AR40197 and AG15052 (to K.W.); NIH Cardiovascular Scientist Training Grant HL07224 (to D.R.P.); and Grant-in-Aid for Scientific Research on Priority Areas (to S.K. and T.F.). R.S. was supported by grants from the American Heart Association Postdoctoral Fellowship Award, Northeast Affiliate and the Uehara Memorial Foundation. N.O. was supported by a Department of Medicine Pilot Project Grant from Boston University. We gratefully acknowledge the technical assistance of S. Tanaka and A. Bialik.

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Authors and Affiliations

  1. Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, Boston, 02118, Massachusetts, USA

    Rei Shibata, Kaori Sato, Yukihiro Takemura, Noriyuki Ouchi & Kenneth Walsh

  2. Department of Medicine, Cardiovascular Medicine Section, Boston University Medical Center, and Myocardial Biology Unit, Boston University School of Medicine, 715 Albany Street, Boston, 02118, Massachusetts, USA

    David R Pimentel

  3. Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2, Yamada-oka, Suita, 565-0871, Osaka, Japan

    Shinji Kihara, Koji Ohashi & Tohru Funahashi

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Supplementary information

Supplementary Fig. 1

Adiponectin deficiency does not affect capillary vessel density. (PDF 153 kb)

Supplementary Fig. 2

Adiponectin deficiency does not affect IL-1β or IL-6 levels. (PDF 200 kb)

Supplementary Fig. 3

The COX-2 inhibitor NS398 does not affect the adiponectin-mediated inhibition of cultured cardiac myocyte and fibroblast apoptosis. (PDF 133 kb)

Supplementary Fig. 4

Adiponectin suppresses LPS-induced TNFα secretion from cardiac fibroblasts through a COX-2-dependent pathway. (PDF 272 kb)

Supplementary Fig. 5

Adiponectin effects in cultured adult rat myocyte cultures. (PDF 562 kb)

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Shibata, R., Sato, K., Pimentel, D. et al. Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2–dependent mechanisms. Nat Med 11, 1096–1103 (2005). https://doi.org/10.1038/nm1295

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