title: Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1/Caveolin-3/STAT3 Signaling in Diabetic Rats.
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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Anesthesiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Haobo
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Hong Kong, China Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Hong Kong, China.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Irwin
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Anesthesiology, The University of Hong Kong, Hong Kong, China zyxia@hku.hk.
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000818:Animals; D051244:Caveolin 3 / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism; D057775:Ischemic Postconditioning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054419:Receptors, Adiponectin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051244:Caveolin 3; D054419:Receptors, Adiponectin; D050796:STAT3 Transcription Factor; C504339:adiponectin receptor 1, rat