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MicroRNAs as New Players in Endocrinology

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Front. Endocrinol. | doi: 10.3389/fendo.2018.00215

MiR-494 contributes to estrogen protection of cardiomyocytes against oxidative stress via targeting NKRF

Zhi-Ping Tang1, Wei Zhao2,  Jian-Kui Du2, Xin Ni2,  Xiao-Yan Zhu2* and  Jian-Qiang Lu1
  • 1School of Kinesiology, Shanghai University of Sport, China
  • 2Second Military Medical University, China

Oxidative stress plays a pivotal role in the initiation and progression of cardiac diseases. Estrogens have been demonstrated to exert pleiotropic cardioprotective effects, among which anti-oxidative stress is one of the key effects linking estrogens to cardioprotection. By using a microRNAs (miRs) microarray screening approach, we discovered an increase in miR-494, which is known to exert cardioprotective effects, in estrogen-treated cardiomyocytes. We hypothesized that the upregulation of miR-494 might contribute to estrogen-mediated cardioprotection against oxidative stress. We found that E2 stimulates miR-494 expression via ERα in both cardiomyocytes and the myocardium of female mice. The miR-494 inhibitor attenuated the protective effect of 17beta-estradiol (E2) against oxidative stress-induced injury in cardiomyocytes. By contrast, the miR-494 mimic protected cardiomyocytes against oxidative stress-induced cardiomyocyte injury. Using real-time PCR, western blot and dual-luciferase reporter gene analyses, we identified nuclear factor kappa B (NF-κB) repressing factor (NKRF) as the miR-494 target in cardiomyocytes. E2 was found to inhibit NKRF, thus activating NF-κB through a miR494-dependent mechanism. In addition, the protective effects of E2 and miR-494 against oxidative stress in cardiomyocytes were eliminated by the NF-κB inhibitor. In summary, this study demonstrates for the first time that estrogen inhibits NKRF expression through ERα-mediated upregulation of miR-494 in cardiomyocytes, leading to the activation of NF-κB, which in turn results in an increase in antioxidative defense. ERα-mediated upregulation of miR-494 may contribute to estrogen protection of cardiomyocytes against oxidative stress.

Keywords: MiR-494;, estrogen;, cardiomyocytes;, Oxidative Stress;, NKRF

Received: 02 Nov 2017; Accepted: 16 Apr 2018.

Edited by:

Yan-ling Wang, Institute of Zoology (CAS), China

Reviewed by:

Kun D. Yi, Syngenta Crop Protection, LLC, United States
Shuangbo Kong, Xiamen University, China  

Copyright: © 2018 Tang, Zhao, Du, Ni, Zhu and Lu. 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 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: Dr. Xiao-Yan Zhu, Second Military Medical University, Shanghai, China, xiaoyanzhu@smmu.edu.cn