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This article is part of the Research Topic

Non-Coding RNAs and Human Diseases

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2018.00734

MiR-499-5p attenuates mitochondrial fission and cell apoptosis via p21 in doxorubicin cardiotoxicity

 Qinggong Wan1, Wei Ding2, Xuejuan Zhang2, Tao Xu1, Xiao-Yu Ji1, Tao Yu1, Wanpeng Yu1, Zhijuan Lin1 and  Jianxun Wang1*
  • 1School of Basic Medical Sciences, Qingdao University, Institute for translational medicine, Qingdao University, China
  • 2Shibei District Comprehensive Internal Medicine, Affiliated Hospital, Qingdao University, China

Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but its cardiotoxicity limits its clinical application. A better understanding of the molecular mechanisms underlying DOX cardiotoxicity will benefit clinical practice and remedy heart failure. Our present study observed that DOX caused cardiomyocyte (H9c2) apoptosis via the induction of abnormal mitochondrial fission. Notably, the expression levels of p21 increased in DOX-treated cardiomyocytes, and the silencing of p21 using siRNA greatly attenuated mitochondrial fission and apoptosis in cardiomyocytes. We also found that miR-499-5p could directly target p21 and attenuated DOX-induced mitochondrial fission and apoptosis. The role of the miR-499-5p-p21 axis in the prevention of DOX cardiotoxicity was also validated in the mice model. DOX treatment induced an upregulation of p21, which induced subsequent abnormal mitochondrial fission and myocardial apoptosis in mouse heart. Adenovirus-harboring miR-499-5p-overexpressing mice exhibited significantly reduced p21 expression, mitochondrial fission and myocardial apoptosis in hearts following DOX administration. The miR-499-5p-overexpressing mice also exhibited improved cardiomyocyte hypertrophy and cardiac function after DOX treatment. However, miR-499-5p was not involved in the DOX-induced apoptosis of cancer cells. Taken together, these findings reveal an emerging role of p21 in the regulation of mitochondrial fission program. miR-499-5p attenuated mitochondrial fission and DOX cardiotoxicity via the targeting of p21. These results provide new evidence for the miR-499-5p-p21 axis in the attenuation of DOX cardiotoxicity. The development of new therapeutic strategies based on the miR-499-5p-p21 axis is a promising path to overcome DOX cardiotoxicity as a chemotherapy for cancer treatment.

Keywords: Doxorubicin, miR-499-5p, p21, cardiotoxicity, mitochondrial, Apoptosis

Received: 06 Oct 2018; Accepted: 22 Dec 2018.

Edited by:

Ge Shan, University of Science and Technology of China, China

Reviewed by:

UDAYAN BHATTACHARYA, Technion Israel Institute of Technology, Israel
Nithyananda Thorenoor, College of Medicine, Pennsylvania State University, United States  

Copyright: © 2018 Wan, Ding, Zhang, Xu, Ji, Yu, Yu, Lin and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Jianxun Wang, Institute for translational medicine, Qingdao University, School of Basic Medical Sciences, Qingdao University, Qingdao, Shandong Province, China, wangjx@qdu.edu.cn