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(Circulation. 2009;119:835-844.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

AMP-Activated Protein Kinase Deficiency Enhances Myocardial Ischemia/Reperfusion Injury but Has Minimal Effect on the Antioxidant/Antinitrative Protection of Adiponectin

Yajing Wang, MD, PhD^*; Erhe Gao, MD, PhD^*; Ling Tao, MD, PhD; Wayne Bond Lau, MD; Yuexin Yuan, PhD; Barry J. Goldstein, MD, PhD; Bernard L. Lopez, MD; Theodore A. Christopher, MD; Rong Tian, MD, PhD; Walter Koch, PhD; Xin-Liang Ma, MD, PhD

From the Department of Emergency Medicine (Y.W., L.T., W.B.L., Y.Y., B.L.L., T.A.C., X.M.), Center for Translational Medicine (E.G., W.K.), Division of Endocrinology, Diabetes, and Metabolic Diseases (B.J.G.), Thomas Jefferson University, Philadelphia, Pa; and Nuclear Magnetic Resonance Laboratory for Physiological Chemistry, Brigham and Women’s Hospital, Boston, Mass (R.T.).

Correspondence to Xin L. Ma, MD, PhD, Department of Emergency Medicine, 1020 Sansom St, Thompson Building, Room 239, Philadelphia, PA 19107. E-mail Xin.Ma{at}Jefferson.edu

Received August 14, 2008; accepted December 11, 2008.

Background— Diabetes increases the morbidity/mortality of ischemic heart disease, but the underlying mechanisms are incompletely understood. Deficiency of both AMP-activated protein kinase (AMPK) and adiponectin occurs in diabetes, but whether AMPK is cardioprotective or a central mediator of adiponectin cardioprotection in vivo remains unknown.

Methods and Results— Male adult mice with cardiomyocyte-specific overexpression of a mutant AMPK₂ subunit (AMPK-DN) or wild-type (WT) littermates were subjected to in vivo myocardial ischemia/reperfusion (MI/R) and treated with vehicle or adiponectin. In comparison to WT, AMPK-DN mice subjected to MI/R endured greater cardiac injury (larger infarct size, more apoptosis, and poorer cardiac function) likely as a result of increased oxidative stress in these animals. Treatment of AMPK-DN mice with adiponectin failed to phosphorylate cardiac acetyl-CoA carboxylase as it did in WT mouse heart. However, a significant portion of the cardioprotection of adiponectin against MI/R injury was retained in AMPK-DN mice. Furthermore, treatment of AMPK-DN mice with adiponectin reduced MI/R-induced cardiac oxidative and nitrative stress to the same degree as that seen in WT mice. Finally, treating AMPK-DN cardiomyocytes with adiponectin reduced simulated MI/R-induced oxidative/nitrative stress and decreased cell death (P<0.01).

Conclusions— Collectively, our results demonstrated that AMPK deficiency significantly increases MI/R injury in vivo but has minimal effect on the antioxidative/antinitrative protection of adiponectin.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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