Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Adiponectin, a circulating adipose-derived cytokine, is downregulated in obese individuals and after myocardial infarction. This study shows that adiponectin reduces infarct size, apoptosis, and TNF-α production in both adiponectin-deficient (APN-KO) and wild-type mice. Adiponectin inhibits apoptosis and TNF-α production in cultured cardiac cells. Dominant negative AMPK reversed the inhibitory effects of adiponectin on apoptosis but had no effect on TNF-α production. Adiponectin induced 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. Adiponectin deficiency in mice resulted in increased infarct size, apoptosis, and TNF-α expression after ischemia-reperfusion. Adiponectin supplementation reduced infarct size, apoptosis, and TNF-α production. Adiponectin inhibited apoptosis through AMPK activation and TNF-α production through COX-2-dependent pathways. Adiponectin also inhibited TNF-α production through COX-2 and PGE2 pathways. These findings suggest that adiponectin has protective effects against myocardial injury through multiple mechanisms. Adiponectin deficiency is associated with increased TNF-α levels and inflammation. Adiponectin supplementation reduced TNF-α levels and improved cardiac function. Adiponectin also reduced infarct size and improved cardiac remodeling. Adiponectin may have therapeutic potential for treating cardiovascular diseases. Adiponectin deficiency is linked to obesity and metabolic disorders. Adiponectin supplementation may be beneficial for patients with cardiovascular diseases. Adiponectin has anti-inflammatory and anti-apoptotic effects. Adiponectin may be used as a therapeutic agent for cardiovascular diseases. Adiponectin deficiency is associated with increased risk of cardiovascular diseases. Adiponectin supplementation may reduce the risk of cardiovascular diseases. Adiponectin has protective effects against myocardial injury. Adiponectin may be used as a therapeutic agent for cardiovascular diseases. Adiponectin deficiency is associated with increased inflammation and apoptosis. Adiponectin supplementation may reduce inflammation and apoptosis. Adiponectin may be used as a therapeutic agent for cardiovascular diseases. Adiponectin has protective effects against myocardial injury. Adiponectin may be used as a therapeutic agent for cardiovascularAdiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Adiponectin, a circulating adipose-derived cytokine, is downregulated in obese individuals and after myocardial infarction. This study shows that adiponectin reduces infarct size, apoptosis, and TNF-α production in both adiponectin-deficient (APN-KO) and wild-type mice. Adiponectin inhibits apoptosis and TNF-α production in cultured cardiac cells. Dominant negative AMPK reversed the inhibitory effects of adiponectin on apoptosis but had no effect on TNF-α production. Adiponectin induced 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. Adiponectin deficiency in mice resulted in increased infarct size, apoptosis, and TNF-α expression after ischemia-reperfusion. Adiponectin supplementation reduced infarct size, apoptosis, and TNF-α production. Adiponectin inhibited apoptosis through AMPK activation and TNF-α production through COX-2-dependent pathways. Adiponectin also inhibited TNF-α production through COX-2 and PGE2 pathways. These findings suggest that adiponectin has protective effects against myocardial injury through multiple mechanisms. Adiponectin deficiency is associated with increased TNF-α levels and inflammation. Adiponectin supplementation reduced TNF-α levels and improved cardiac function. Adiponectin also reduced infarct size and improved cardiac remodeling. Adiponectin may have therapeutic potential for treating cardiovascular diseases. Adiponectin deficiency is linked to obesity and metabolic disorders. Adiponectin supplementation may be beneficial for patients with cardiovascular diseases. Adiponectin has anti-inflammatory and anti-apoptotic effects. Adiponectin may be used as a therapeutic agent for cardiovascular diseases. Adiponectin deficiency is associated with increased risk of cardiovascular diseases. Adiponectin supplementation may reduce the risk of cardiovascular diseases. Adiponectin has protective effects against myocardial injury. Adiponectin may be used as a therapeutic agent for cardiovascular diseases. Adiponectin deficiency is associated with increased inflammation and apoptosis. Adiponectin supplementation may reduce inflammation and apoptosis. Adiponectin may be used as a therapeutic agent for cardiovascular diseases. Adiponectin has protective effects against myocardial injury. Adiponectin may be used as a therapeutic agent for cardiovascular