Abstract: AIM:To investigate whether TNF-α blockade may augment circulatory APN, thus exerting the cardioprotective effect against myocardial ischemia/reperfusion (MI/R) injury via APN upregulation. METHODS: Adult male mice and ob/ob mice were subjected to 30 min of MI followed by R. Animals were injected with TNF-α antagonist or vehicle 10 min before R. Mice were divided into six groups: sham group, MI/R+vehicle group, MI/R+TNF-α blockade group, ob/ob sham group, ob/ob+MI/R+vehicle group, and ob/ob+MI/R+TNF-α blockade group. RESULTS: Compared with that of vehicle, elevation of plasma APN concentration at 3 h, 8 h, 1 day, and 3 days after MI/R was observed in TNF-α antagonist treatment group. Administration of TNF-α antagonist ameliorated MI/R injury in WT mice, evidenced by consistently augmented cardiac function, reduced infarct size and apoptosis. TNF-α antagonist failed to augment APN levels or exert significant cardioprotective effects in ob/ob mice, but administration of globular domain of adiponectin (gAPN) ameliorated MI/R injury. CONCLUSION: TNF-α is responsible for the decrease of APN during MI/R. The cardioprotective effect of TNF-α neutralization is partially exerted via upregulation of APN.