MiRNA-30e mediated cardioprotection of ACE2 in rats with Doxorubicin-induced heart failure through inhibiting cardiomyocytes autophagy

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• 作者：Lei Lai ; Junzhu Chen ; ^{c_junzhu@163.com} ; Ningfu Wang ; Gangjie Zhu ; Xu Duan ; Feng Ling
• 关键词：rhACE2 ; Autophagy ; Beclin-1 ; LC3-II/I ; Caspase-3
• 刊名：Life Sciences
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：169
• 期：Complete
• 页码：69-75
• 全文大小：975 K
• 卷排序：169

文摘

miRNAs are a class of small non-coding RNAs that has been proved to be involved in cardioprotection. The present study was to detect role of miR-30e in cardiac-protective action of ACE2 (angiotensin-converting enzyme 2).MethodsSprague Dawley rats were divided into 3 groups and received treatment for a total of 6 weeks: group1, normal rats; group2, Doxorubicin-induced heart cardiomyopathy (DHC) rats; and group3, rhACE2 (recombinant human ACE2) treated DHC rats. Doxorubicin was discontinuously administered via intraperitoneal injection. Primary cardiomyocytes and H9C2 cell line were used for in vitro experiments. MiR-30a, miR-30c and miR-30e expression were determined using qRT-PCR. Expression of autophagy associated gene expression including Beclin-1 and LC3 II/I were determined using western blot. Cell apoptosis was evaluated using TUNEL assay.ResultsAdministration of ACE2 suppressed harmful action of Doxorubicin and caused a significant improvement of left ventricular contractility function, upregulation in miR-30 (a, c and e) expression, and inhibition in Beclin-1 expression and LC3-II/I ratio. This was supported by results of Ad-ACE2-incubated primary cardiomyocytes. By manipulating miR-30e expression in H9C2 cells, we observed that miR-30e regulated Beclin-1 expression via inhibiting its 3’UTR activity. MiR-30e mimic treatment resulted in downregulation of Beclin-1 and protected primary cardiomyocytes against apoptosis. Moreover, silencing miR-30e induced cardiomyocytes apoptosis was abrogated by ACE2 overexpresssion. This was further confirmed by in vivo DHC rat experiments that showed that co-injected ACE2 and miR-30 inhibitor reduced cardiac function.ConclusionIn summary, administration of ACE2 attenuates Doxorubicin-induced cardiac dysfunction via preservation of cardiomyocytes autophagy in a miR-30e/beclin-1 signal pathway.