Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1/Caveolin-3/STAT3 Signaling in Diabetic Rats

Citation:

H. Li, W. Yao, Z. Liu, A. Xu, Y. Huang, X. L. Ma, M. G. Irwin, and Z. Xia. 2016. “Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1/Caveolin-3/STAT3 Signaling in Diabetic Rats.” DiabetesDiabetesDiabetes, 65, Pp. 942-55.

Abstract:

Signal transducer and activator of transcription 3 (STAT3) activation is key for ischemic postconditioning (IPo) to attenuate myocardial ischemia-reperfusion injury (MIRI), but IPo loses cardioprotection in diabetes in which cardiac STAT3 activation is impaired and adiponectin (APN) reduced. 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(-/-)) mice subjected to 30 min coronary occlusion, followed by 2 or 24 h of reperfusion. Hypoxic postconditioning-induced protection against hypoxia/reoxygenation injury was lost in Adipo(-/-) 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.

Notes:

1939-327xLi, HaoboYao, WeifengLiu, ZipengXu, AiminHuang, YuMa, Xin-LiangIrwin, Michael GXia, ZhengyuanJournal ArticleUnited StatesDiabetes. 2016 Apr;65(4):942-55. doi: 10.2337/db15-0782. Epub 2015 Dec 30.