Zhou Bin, Lei Shaoqing, Xue Rui, Leng Yan, Xia Zhengyuan, Xia Zhong-Yuan
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Anesthesiology, University of Hong Kong, Hong Kong, China.
Clin Sci (Lond). 2017 May 22;131(11):1161-1178. doi: 10.1042/CS20170052. Print 2017 Jun 1.
IPO (ischaemic post-conditioning) is a promising method of alleviating myocardial IR (ischaemia-reperfusion) injury; however, IPO-mediated cardioprotection is lost in diabetic hearts via mechanisms that remain largely unclear. We hypothesized that decreased cardiac expression of DJ-1, a positive modulator of autophagy, compromises the effectiveness of IPO-induced cardioprotection in diabetic rats. Diabetic rats subjected to myocardial IR (30 min of coronary artery occlusion followed by 120 min of reperfusion) exhibited more severe myocardial injury, less cardiac autophagy, lower DJ-1 expression and AMPK (adenosine monophosphate-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway activity than non-diabetic rats. IPO significantly attenuated myocardial injury and up-regulated cardiac DJ-1 expression, AMPK/mTOR activity and autophagy in non-diabetic rats but not in diabetic rats. AAV9 (adeno-associated virus 9)-mediated cardiac DJ-1 overexpression as well as pretreatment with the autophagy inducer rapamycin restored IPO-induced cardioprotection in diabetic rats, an effect accompanied by AMPK/mTOR activation and autophagy up-regulation. Combining HPO (hypoxic post-conditioning) with DJ-1 overexpression markedly attenuated HR (hypoxia-reoxygenation) injury in H9c2 cells with high glucose (HG, 30 mM) exposure, accompanied by AMPK/mTOR signalling activation and autophagy up-regulation. The DJ-1 overexpression-mediated preservation of HPO-induced cardioprotection was completely inhibited by the AMPK inhibitor compound C (CC) and the autophagy inhibitor 3-MA (3-methyladenine). Thus, decreased cardiac DJ-1 expression, which results in impaired AMPK/mTOR signalling and decreased autophagy, could be a major mechanism underlying the loss of IPO-induced cardioprotection in diabetes.
缺血后处理（IPO）是一种很有前景的减轻心肌缺血再灌注（IR）损伤的方法；然而，IPO介导的心脏保护作用在糖尿病心脏中丧失，其机制在很大程度上仍不清楚。我们推测，自噬的正向调节因子DJ-1在心脏中的表达降低，会损害IPO诱导的糖尿病大鼠心脏保护作用的有效性。与非糖尿病大鼠相比，经历心肌IR（冠状动脉闭塞30分钟，随后再灌注120分钟）的糖尿病大鼠表现出更严重的心肌损伤、更少的心脏自噬、更低的DJ-1表达以及腺苷酸活化蛋白激酶（AMPK）/雷帕霉素靶蛋白（mTOR）信号通路活性。IPO可显著减轻非糖尿病大鼠的心肌损伤，并上调心脏DJ-1表达、AMPK/mTOR活性和自噬，但对糖尿病大鼠无效。腺相关病毒9（AAV9）介导的心脏DJ-1过表达以及自噬诱导剂雷帕霉素预处理可恢复IPO诱导的糖尿病大鼠心脏保护作用，这一效应伴随着AMPK/mTOR激活和自噬上调。将低氧后处理（HPO）与DJ-1过表达相结合，可显著减轻高糖（HG，30 mM）处理的H9c2细胞中的缺氧复氧（HR）损伤，同时伴有AMPK/mTOR信号激活和自噬上调。DJ-1过表达介导的HPO诱导的心脏保护作用的维持被AMPK抑制剂化合物C（CC）和自噬抑制剂3-甲基腺嘌呤（3-MA）完全抑制。因此，心脏DJ-1表达降低导致AMPK/mTOR信号受损和自噬减少，可能是糖尿病中IPO诱导的心脏保护作用丧失的主要机制。
