This study investigates the role of adiponectin in myocardial remodeling and protection against ischemia-reperfusion injury. Adiponectin, a cytokine derived from adipose tissue, is downregulated in obese individuals and after myocardial infarction. The researchers found that adiponectin-deficient mice (APN-KO) showed increased myocardial infarct size, myocardial apoptosis, and tumor necrosis factor (TNF)-α expression compared to wild-type mice. Administration of adiponectin reduced these adverse effects in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-α production. AMP-activated protein kinase (AMPK) signaling was involved in the antiapoptotic effects of adiponectin, as dominant negative AMPK reversed the inhibitory effects of adiponectin on apoptosis but not on TNF-α production. Adiponectin also induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E2 (PGE2), and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-α production and infarct size. These findings suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.This study investigates the role of adiponectin in myocardial remodeling and protection against ischemia-reperfusion injury. Adiponectin, a cytokine derived from adipose tissue, is downregulated in obese individuals and after myocardial infarction. The researchers found that adiponectin-deficient mice (APN-KO) showed increased myocardial infarct size, myocardial apoptosis, and tumor necrosis factor (TNF)-α expression compared to wild-type mice. Administration of adiponectin reduced these adverse effects in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-α production. AMP-activated protein kinase (AMPK) signaling was involved in the antiapoptotic effects of adiponectin, as dominant negative AMPK reversed the inhibitory effects of adiponectin on apoptosis but not on TNF-α production. Adiponectin also induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E2 (PGE2), and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-α production and infarct size. These findings suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.