Role of class Ⅰ histone deacetylase in myocardial ischemia-reperfusion injury in diabetic rats and the relationship with AMPK∕mTOR signaling pathway
10.3760∕cma.j.issn.0254-1416.2018.07.010
- VernacularTitle:Ⅰ型组蛋白去乙酰化酶在糖尿病大鼠心肌缺血再灌注损伤中的作用及其与AMPK∕mTOR信号通路的关系
- Author:
Wei LI
1
;
Yan LENG
;
Qingtao MENG
;
Yang WU
;
Rong CHEN
;
Huimin LIU
;
Zhongyuan XIA
Author Information
1. 430060,武汉大学人民医院麻醉科
- Keywords:
Histone deacetylase;
Autophagy;
Diabetes mellitus;
Myocardial reperfusion in-jury;
Protein-serine-threonine kinases;
Receptor-interacting protein serine-threonine kinases
- From:
Chinese Journal of Anesthesiology
2018;38(7):808-812
- CountryChina
- Language:Chinese
-
Abstract:
Objective To evaluate the role of classⅠhistone deacetylase (HDAC) in myocardial ischemia-reperfusion (I∕R) injury in diabetic rats and the relationship with adenosine monophosphate-acti- vated protein kinase (AMPK)∕mammalian target of rapamycin (mTOR) signaling pathway. Methods SPF healthy adult male Sprague-Dawley rats, weighing 210-220 g, were used in this study. Type I diabetes mellitus was induced by single intraperitoneal injection of streptozotocin dissolved in citrate buffer 60 mg∕kg, and 8 weeks later the rats with type I diabetes mellitus were used for experiment. Forty-eight diabetic rats were divided into 4 groups (n＝12 each) by using a random number table method: sham operation group (group S), myocardial I∕R group (group I∕R), myocardial I∕R plus class I HDAC inhibitor MS-275 group (group I∕R+MS) and myocardial I∕R plus MS-275 plus AMPK inhibitor Compound C group ( group I∕R+MS+CC). Myocardial I∕R was induced by ligation of the left anterior descending branch of the coronary ar-tery for 45 min followed by 180 min of reperfusion in anesthetized rats. In group I∕R+MS, MS-275 10 mg∕kg was intraperitoneally injected once a day for 7 consecutive days, and myocardial I∕R was produced after the end of administration. AMPK inhibitor Compound C 0. 5 mg∕kg was intravenously injected at 30 min before ischemia in group I∕R+MS+CC. Six rats were sacrificed at the end of reperfusion for determina-tion of myocardial infarct size. Another 6 rats were selected at the end of reperfusion and sacrificed for deter-mination of the level of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in serum (by en-zyme-linked immunosorbent assay), expression of AMPK, phosphorylated AMPK ( p-AMPK), mTOR, phosphorylated mTOR (p-mTOR), ubiquitin-binding protein P62 (P62), microtubule-associated protein 1 light chain 3 Ⅰ(LC3 Ⅰ) and LC3Ⅱ in myocardial tissues (by Western blot). The ratios of p-AMPK∕AMPK, p-mTOR∕mTOR and LC3Ⅱ∕Ⅰwere calculated. Results Compared with group S, the myocardial infarct size and levels of serum CK-MB and LDH were significantly increased in I∕R, I∕R+MS and I∕R+M+CC groups, the ratios of p-AMPK∕AMPK and LC3Ⅱ∕Ⅰwere significantly increased, p-mTOR∕mTOR ratio was decreased, and P62 expression was down-regulated in group I∕R+MS (P＜0. 05), and no significant change was found in p-AMPK∕AMPK ratio, p-mTOR∕mTOR ratio, LC3Ⅱ∕Ⅰ ratio or P62 expression in I∕R and I∕R+M+CC groups (P＞0. 05). Compared with group I∕R, the myocardial infarct size and levels of serum CK-MB and LDH were significantly decreased, the ratios of p-AMPK∕AMPK and LC3Ⅱ∕Ⅰwere in-creased, p-mTOR∕mTOR ratio was decreased, and P62 expression was down-regulated in group I∕R+MS (P＜0. 05), and no significant change was found in the parameters mentioned above in group I∕R+M+CC (P＞0. 05). Compared with group I∕R+MS, the myocardial infarct size and levels of serum CK-MB and LDH were significantly increased, the ratios of p-AMPK∕AMPK and LC3Ⅱ∕Ⅰ were decreased, p-mTOR∕mTOR ratio was increased, and P62 expression was up-regulated in group I∕R+M+CC ( P＜0. 05). Con-clusion Class Ⅰ HDAC is involved in myocardial I∕R injury through enhancing AMPK∕mTOR signaling pathway-regulated level of autophagy in diabetic rats.
