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We found that IPo increased postischemic cardiomyocyte-derived APN, activated mitochondrial STAT3 (mitoSTAT3), improved mitochondrial function, and attenuated MIRI in wild-type but not in APN knockout (Adipo\u2212\/\u2212) mice subjected to 30 min coronary occlusion, followed by 2 or 24 h of reperfusion. Hypoxic postconditioning\u2013induced protection against hypoxia\/reoxygenation injury was lost in Adipo\u2212\/\u2212 cardiomyocytes but restored by recombinant APN, but this APN beneficial effect was abolished by specific STAT3 or APN receptor 1 (AdipoR1) gene knockdown, or caveolin-3 (Cav3) disruption. APN activated cardiac STAT3 and restored IPo cardioprotection in 4-week diabetic rats where AdipoR1 and Cav3 were functionally interactive but not in 8-week diabetic rats whose cardiac Cav3 was severely reduced and AdipoR1\/Cav3 signaling impaired. We concluded that IPo activates mitoSTAT3 through APN\/AdipoR1\/Cav3 pathway to confer cardioprotection, whereas in diabetes, IPo loses cardioprotection due to impaired APN\/AdipoR1\/Cav3 signaling. Therefore, effective means that may concomitantly activate APN and repair APN signaling (i.e., AdipoR1\/Cav3) in diabetes may represent promising avenues in the treatment of MIRI in diabetes.<\/jats:p>","DOI":"10.2337\/db15-0782","type":"journal-article","created":{"date-parts":[[2015,12,31]],"date-time":"2015-12-31T03:43:57Z","timestamp":1451533437000},"page":"942-955","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":73,"title":["Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1\/Caveolin-3\/STAT3 Signaling in Diabetic Rats"],"prefix":"10.2337","volume":"65","author":[{"given":"Haobo","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China"},{"name":"Department of Anesthesiology, The University of Hong Kong, Hong Kong, 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