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(Circulation. 2007;116:2809-2817.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Cardioprotective Effects of Short-Term Caloric Restriction Are Mediated by Adiponectin via Activation of AMP-Activated Protein Kinase

Ken Shinmura, MD, PhD; Kayoko Tamaki, BS; Kiyomi Saito, PhD; Yasuko Nakano, PhD; Takashi Tobe, PhD; Roberto Bolli, MD

From the Division of Geriatric Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan (K. Shinmura, K.T.); Department of Medicinal Information, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan (K. Saito, Y.N., T.T.); and Institute of Molecular Cardiology, University of Louisville, Louisville, Ky (R.B.).

Correspondence to Ken Shinmura, MD, PhD, FAHA, Division of Geriatric Medicine, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 160-8582. E-mail shimmura{at}sc.itc.keio.ac.jp

Received July 24, 2006; accepted September 21, 2007.

Background— Overeating and obesity are major health problems in developed countries. Caloric restriction (CR) can counteract the deleterious aspects of obesity-related diseases and prolong lifespan. We have demonstrated that short-term CR improves myocardial ischemic tolerance and increases adiponectin levels. Here, we investigated the specific role of adiponectin in CR-induced cardioprotection.

Methods and Results— Adiponectin antisense transgenic (Ad-AS) mice and wild-type (WT) mice were randomly assigned to a group fed ad libitum and a CR group (90% of caloric intake of ad libitum for 3 weeks, then 65% for 2 weeks). Isolated perfused mouse hearts were subjected to 25 minutes of ischemia, followed by 60 minutes of reperfusion. CR increased serum adiponectin levels by 84% in WT mice. Gel filtration analysis of the oligomeric complex distribution showed that CR produced a marked increase in the high–molecular-weight complex of adiponectin in WT mice; in contrast, CR did not change serum adiponectin levels or their oligomeric pattern in Ad-AS mice. CR improved the recovery of left ventricular function after ischemia/reperfusion and limited infarct size in WT mice; these effects were completely abrogated in Ad-AS mice. CR also increased the phosphorylated form of AMP-activated protein kinase and acetyl-CoA carboxylase in WT but not in Ad-AS mice. Recombinant adiponectin restored CR-induced cardioprotection in Ad-AS mice, and inhibition of AMP-activated protein kinase phosphorylation completely abrogated CR-induced cardioprotection in WT mice.

Conclusion— The cardioprotective effects of short-term CR are mediated by increased production of adiponectin and the associated activation of AMP-activated protein kinase.

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