Obestatin attenuated doxorubicin-induced cardiomyopathy via enhancing long noncoding Mhrt RNA expression.
OBJECTIVE
The emergence of side-effect of doxorubicin in cardiomyopathy and heart failure has led to the search for diverse strategies to prevent its cytotoxic effects. This study was to determine the role of obestatin on doxorubicin-induced cardiomyocytes apoptosis and possible underlying mechanism.


METHODS
Sprague Dawley rats were divided into 3 groups and received treatment for a total of 6 weeks: group1, untreated normal rats; group2, Doxorubicin-induced heart cardiomyopathy (DC) rats; and group3, obestatin treated HC rats. Doxorubicin (2.5mg/kg) or obestatin (100μg/kg/d) were discontinuously administered via intraperitoneal injection. Primary cardiomyocytes and H9C2 cell line were used for in vitro experiments. Mhrt and Nrf2 (nuclear factor erythroid 2 -related factor 2) mRNA expressions were determined using qRT-PCR. Expression of Nrf2 protein was determined using western blotting. TUNEL assay was performed to evaluate cell apoptosis.


RESULTS
Administration of obestatin significantly improved doxorubicin-induced dysfunction of left ventricular contractility function, moreover, resulted in upregulation of Mhrt and Nrf2 in failing myocardial tissue. Co-incubation of obestatin and doxorubicin in primary cardiomyocytes also enhanced Mhrt and Nrf2 expression as well as prevented cell apoptosis in comparison with doxorubicin only. Manipulation of cellular Mhrt by pcDNA-Mhrt or si-Mhrt transfection positively regulated Nrf2 expression in doxorubicin-incubated cardiomyocytes. Silencing Mhrt reversed cardioprotective effects of obestatin both in vivo and in vitro.


CONCLUSIONS
Administration of obestatin attenuates doxorubicin-induced cardiac dysfunction via preservation of cardiomyocytes apoptosis in a Mhrt-Nrf2 dependent pathway.
Department of Gerontology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Anhui Institute of Cardiovascular Disease, Hefei 230001, China.
Hong-Qi
HQ
Li
Department of Neurology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Hefei 230001, China.
Yuan-Bo
YB
Wu
Department of Gerontology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Anhui Institute of Cardiovascular Disease, Hefei 230001, China.
Chang-Sen
CS
Yin
Department of Gerontology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Anhui Institute of Cardiovascular Disease, Hefei 230001, China.
Li
L
Chen
Department of Gerontology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Anhui Institute of Cardiovascular Disease, Hefei 230001, China.
Qi
Q
Zhang
Department of Gerontology, Affiliated Anhui Provincial Hospital, Anhui Medical University, Anhui Institute of Cardiovascular Disease, Hefei 230001, China. Electronic address: hlqae3005@126.com.
Li-Qun
LQ
Hu
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D004317:Doxorubicin; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D054439:Ghrelin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D017207:Rats, Sprague-Dawley
D002316:Cardiotonic Agents; D054439:Ghrelin; D051267:NF-E2-Related Factor 2; D062085:RNA, Long Noncoding; C000613726:long non-coding RNA Mhrt, rat; D004317:Doxorubicin
Caspase-3; Cell apoptosis; Mhrt; Nrf2; Obestatin