Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1/Caveolin-3/STAT3 Signaling in Diabetic Rats
Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1/Caveolin-3/STAT3 Signaling in Diabetic Rats
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DOI：
10.2337/db15-0782
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发表时间：
2016-04-01
期刊：
影响因子：
7.7
通讯作者：
Xia, Zhengyuan
中科院分区：
文献类型：
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作者：
Li, Haobo;Yao, Weifeng;Xia, Zhengyuan
信号换能器和转录激活因子3 （STAT3）的激活是缺血后适应（IPo）减轻心肌缺血再灌注损伤（MIRI）的关键，但在心脏STAT3激活受损和脂联素（APN）减少的糖尿病中，IPo失去了心脏保护作用。我们发现IPo增加了缺血后心肌细胞衍生的APN，激活了线粒体STAT3 (mitoSTAT3)，改善了线粒体！在野生型（APN敲除Adipo(-/-)）小鼠中，经30分钟冠状动脉闭塞，然后再灌注2或24小时，MIRI减弱，而在APN敲除（Adipo(-/-)）小鼠中则没有。在Adipo（-/-）心肌细胞中，缺氧后适应诱导的对缺氧/再氧化损伤的保护作用丧失，但通过重组APN恢复，但这种APN的有益作用被特异性STAT3或APN受体1 （AdipoR1）基因敲低或cavolin -3 （Cav3）破坏而消除。在AdipoR1和Cav3功能相互作用的4周糖尿病大鼠中，APN激活心脏STAT3并恢复IPo心脏保护作用，但在心脏Cav3严重降低和AdipoR1/Cav3信号通路受损的8周糖尿病大鼠中则没有。我们得出结论，IPo通过APN/AdipoR1/Cav3通路激活mitoSTAT3，赋予心脏保护作用，而在糖尿病中，IPo由于APN/AdipoR1/Cav3信号通路受损而失去心脏保护作用。因此，在糖尿病中同时激活APN和修复APN信号的有效手段（即AdipoR1/Cav3）可能代表了治疗糖尿病MIRI的有希望的途径。
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 mitochondria! 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.