Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China.
J Diabetes Res. 2020 Apr 3;2020:2408240. doi: 10.1155/2020/2408240. eCollection 2020.
Diabetic hearts are more susceptible to myocardial ischemia/reperfusion (I/R) injury and less sensitive to ischemic postconditioning (IPostC), but the underlying mechanisms remain unclear. PKC2 is preferentially overactivated in diabetic myocardium, in which autophagy status is abnormal. This study determined whether hyperglycemia-induced PKC2 activation resulted in autophagy abnormality and compromised IPostC cardioprotection in diabetes. We found that diabetic rats showed higher cardiac PKC2 activation and lower autophagy than control at baseline. However, myocardial I/R further increased PKC2 activation and promoted autophagy status in diabetic rats. IPostC significantly attenuated postischemic infarct size and CK-MB, accompanied with decreased PKC2 activation and autophagy in control but not in diabetic rats. Pretreatment with CGP53353, a selective inhibitor of PKC2, attenuated myocardial I/R-induced infarction and autophagy and restored IPostC-mediated cardioprotection in diabetes. Similarly, CGP53353 could restore hypoxic postconditioning (HPostC) protection against hypoxia reoxygenation- (HR-) induced injury evidenced by decreased LDH release and JC-1 monomeric cells and increased cell viability. These beneficial effects of CGP53353 were reversed by autophagy inducer rapamycin, but could be mimicked by autophagy inhibitor 3-MA. It is concluded that selective inhibition of PKC2 could attenuate myocardial I/R injury and restore IPostC-mediated cardioprotection possibly through modulating autophagy in diabetes.
糖尿病心脏更容易受到心肌缺血/再灌注（I/R）损伤，对缺血后处理（IPostC）的敏感性降低，但潜在机制尚不清楚。PKC2 在糖尿病心肌中优先过度激活，其自噬状态异常。本研究旨在确定高血糖诱导的 PKC2 激活是否导致自噬异常，并损害糖尿病中的 IPostC 心脏保护作用。我们发现，与对照组相比，糖尿病大鼠在基线时表现出更高的心脏 PKC2 激活和更低的自噬。然而，心肌 I/R 进一步增加了糖尿病大鼠的 PKC2 激活并促进了自噬状态。IPostC 显著减轻了缺血后梗死面积和 CK-MB，同时降低了对照组而非糖尿病大鼠的 PKC2 激活和自噬。PKC2 的选择性抑制剂 CGP53353 预处理可减轻心肌 I/R 引起的梗死和自噬，并恢复糖尿病中 IPostC 介导的心脏保护作用。同样，CGP53353 可以恢复低氧后处理（HPostC）对缺氧再复氧-（HR-）诱导损伤的保护作用，表现为 LDH 释放和 JC-1 单体细胞减少，细胞活力增加。CGP53353 的这些有益作用被自噬诱导剂雷帕霉素逆转，但可被自噬抑制剂 3-MA 模拟。因此，选择性抑制 PKC2 可减轻心肌 I/R 损伤，并通过调节糖尿病中的自噬来恢复 IPostC 介导的心脏保护作用。
