The TIR/BB-loop mimetic AS-1 prevents Ang II-induced hypertensive cardiac hypertrophy via NF-\u03baB dependent downregulation of miRNA-143

Juan Song,Qifei Xie,Yi Lu,Chen Shao,Zhongqun Wang,Rui Chen,Ping Yang,Chen Qiao,Peijing Liu,Lin Wang,Jinchuan Yan

doi:10.1038/s41598-019-42936-x

Abstract

Untreated pathological cardiac hypertrophy, which can be caused by sustained systemic hypertension, may lead to heart failure. In the present study, we investigated whether AS-1 had attenuating effects on hypertension-induced cardiac hypertrophy, and whether this process was mediated by the regulation of miRNA-143. To induce the hypertrophic response in vitro, cardiomyocytes were stimulated with Ang II for 24hs. AS-1 administration strongly attenuated Ang II-induced hypertrophic response of cardiomyocytes. Chronical infusion of Ang II via implanted osmotic mini-pump induced increased blood pressure and cardiac hypertrophy in vivo. AS-1 administration attenuated hypertension-induced cardiac hypertrophy by, at least in part, inhibin of MAPK signaling. We observed, for the first time, upregulated expression of miRNA-143 in Ang II-induced cardiomyocytes, and inhibition of miRNA-143 significantly reduced the Ang II-induced hypertrophic responses. Importantly, AS-1 administration diminished the Ang II-induced upregulation of miRNA-143. Overexpression of miRNA-143 abolished the attenuating effects of AS-1 on Ang II-induced hypertrophic response of cardiomyocytes. Additionally, AS-1 administration abrogates Ang II-induced nuclear translocation of p50 NF-κB subunit in hypertrophic cardiomyocytes. Application of NF-κB inhibitor significantly suppressed Ang II-induced upregulation of miRNA-143. Our data suggest a novel mechanism by which AS-1 attenuates Ang II-induced hypertrophic response through downregulation miRNA-143 expression in a NF-κB-dependent manner.

Highlights

Cardiac hypertrophy is an adaptive response of many cardiac diseases, including hypertension, valvular dysfunction and myocardial infarction[1,2]
The mechanisms of hypertension to cardiac hypertrophy are still elusive, overwhelming evidence indicates that altered expressions of miRNAs might be involved in increased blood pressure5. miRNA-143 has been identified as an essential player in hypertension by regulating vascular smooth muscle cells (VSMCs) activities
After infusion of Angiotensin II (Ang II) for 4 weeks, we observed significantly increased blood pressures in vivo, as compared with age-matched sham control mice (Fig. 1)

Summary

Introduction

Cardiac hypertrophy is an adaptive response of many cardiac diseases, including hypertension, valvular dysfunction and myocardial infarction[1,2]. Among these diseases, hypertrophic responses are initially induced by pressure or volume overload[3]. During the development of mammalian hearts, biosynthesis of miRNAs, including miRNA-143/145, is essential by promoting cell differentiation[8] In addition to their functions in cardiovascular development, a wealth of recent studies demonstrated dysregulated expression of miRNAs in many cardiovascular diseases[9,10]. Current studies of therapeutic effects of AS-1 on cardiac hypertrophy are exclusively using the TAC-induced hypertrophic mouse model without affecting blood pressure[18]. AS-1 administration attenuated Ang II-induced hypertrophy by suppressing NF-κB-dependent miRNA-143 expression

Methods

Results

Conclusion