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

Nature Medicinevolume 11, pages1096–1103 (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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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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Correspondence toNoriyuki Ouchi orKenneth Walsh.

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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 Med11, 1096–1103 (2005). https://doi.org/10.1038/nm1295

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