Journal
LIFE SCIENCES
Volume 169, Issue -, Pages 69-75Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2016.09.006
Keywords
rhACE2; Autophagy; Beclin-1; LC3-II/I; Caspase-3
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Objective: 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). Methods: Sprague 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 Beclin1 and LC3 II/I were determined using western blot. cell apoptosis was evaluated using TUNEL assay. Results: Administration of ACE2 suppressed harmful action of Doxorubicin and caused a significant improvement of leftventricular 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. Conclusion: In summary, administration ofACE2 attenuates Doxorubicin-induced cardiac dysfunction via preservation of cardiomyocytes autophagy in a miR-30e/beclin-1 signal pathway. (C) 2016 Elsevier Inc. All rights reserved.
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