Selective Inhibition of PKC beta 2 Restores Ischemic Postconditioning-Mediated Cardioprotection by Modulating Autophagy in Diabetic Rats
Selective Inhibition of PKC beta 2 Restores Ischemic Postconditioning-Mediated Cardioprotection by Modulating Autophagy in Diabetic Rats
复制标题
选择性抑制 PKC beta 2 通过调节糖尿病大鼠的自噬恢复缺血后处理介导的心脏保护作用
DOI：
10.1155/2020/2408240
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发表时间：
2020
影响因子：
4.3
通讯作者：
Lei Shaoqing
中科院分区：
文献类型：
--
作者：
Wang Yafeng;Zhou Lu;Su Wating;Huang Fengnan;Zhang Yuan;Xia Zhong-yuan;Xia Zhengyuan;Lei Shaoqing
糖尿病心脏对心肌缺血/再灌注（I/R）损伤更敏感，对缺血后适应（IPostC）不敏感，但其潜在机制尚不清楚。PKCβ2在糖尿病心肌中优先过度激活，自噬状态异常。本研究确定了高血糖诱导的PKCβ2激活是否导致糖尿病患者自噬异常和IPostC心脏保护功能受损。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PKCβ2激活和更低的自噬。然而，心肌I/R进一步增加PKCβ2的激活，促进糖尿病大鼠的自噬状态。IPostC显著降低了缺血后梗死的大小和CK - MB，同时降低了PKCβ2的活化和自噬，但在糖尿病大鼠中没有。用PKCβ2选择性抑制剂CGP53353预处理，可减轻I/R诱导的心肌梗死和自噬，恢复IPostC介导的糖尿病心脏保护。同样，CGP53353可以恢复缺氧后适应（HPostC）对缺氧再氧化（HR‐）诱导的损伤的保护作用，这可以通过降低LDH释放和JC‐1单体细胞以及提高细胞活力来证明。CGP53353的这些有益作用被自噬诱导剂雷帕霉素逆转，但可以被自噬抑制剂3‐MA模拟。由此可见，选择性抑制PKCβ2可能通过调节糖尿病患者的自噬来减轻心肌I/R损伤并恢复IPostC介导的心脏保护。
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. PKCβ2 is preferentially overactivated in diabetic myocardium, in which autophagy status is abnormal. This study determined whether hyperglycemia‐induced PKCβ2 activation resulted in autophagy abnormality and compromised IPostC cardioprotection in diabetes. We found that diabetic rats showed higher cardiac PKCβ2 activation and lower autophagy than control at baseline. However, myocardial I/R further increased PKCβ2 activation and promoted autophagy status in diabetic rats. IPostC significantly attenuated postischemic infarct size and CK‐MB, accompanied with decreased PKCβ2 activation and autophagy in control but not in diabetic rats. Pretreatment with CGP53353, a selective inhibitor of PKCβ2, 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 PKCβ2 could attenuate myocardial I/R injury and restore IPostC‐mediated cardioprotection possibly through modulating autophagy in diabetes.