MiR-154-5p Functions as an Important Regulator of Angiotensin II-Mediated Heart Remodeling.

Lin Dou,Jun Guo,Tao Shen,Que Wang,Weiqing Tang,Mingjing Yan,Xiaoxue Yu,Jian Li,Yong Man,Kaiyi Zhu,Siming Wang,Xiuqing Huang

doi:10.1155/2019/8768164

Lin Dou, Jun Guo + Show 10 more

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https://doi.org/10.1155/2019/8768164

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Abstract

Chronic hypertension, valvular heart disease, and heart infarction cause cardiac remodeling and potentially lead to a series of pathological and structural changes in the left ventricular myocardium and a progressive decrease in heart function. Angiotensin II (AngII) plays a key role in the onset and development of cardiac remodeling. Many microRNAs (miRNAs), including miR-154-5p, may be involved in the development of cardiac remolding, but the underlying molecular mechanisms remain unclear. We aimed to characterize the function of miR-154-5p and reveal its mechanisms in cardiac remodeling induced by AngII. First, angiotensin II led to concurrent increases in miR-154-5p expression and cardiac remodeling in adult C57BL/6J mice. Second, overexpression of miR-154-5p to a level similar to that induced by AngII was sufficient to trigger cardiomyocyte hypertrophy and apoptosis, which is associated with profound activation of oxidative stress and inflammation. Treatment with a miR-154-5p inhibitor noticeably reversed these changes. Third, miR-154-5p directly inhibited arylsulfatase B (Arsb) expression by interacting with its 3′-UTR and promoted cardiomyocyte hypertrophy and apoptosis. Lastly, the angiotensin type 1 receptor blocker telmisartan attenuated AngII-induced cardiac hypertrophy, apoptosis, and fibrosis by blocking the increase in miR-154-5p expression. Moreover, upon miR-154-5p overexpression in isolated cardiomyocytes, the protective effect of telmisartan was partially abolished. Based on these results, increased cardiac miR-154-5p expression is both necessary and sufficient for AngII-induced cardiomyocyte hypertrophy and apoptosis, suggesting that the upregulation of miR-154-5p may be a crucial pathological factor and a potential therapeutic target for cardiac remodeling.

Highlights

Cardiac remodeling is an adaptive response to pathophysiological stimuli, such as ischemia/reperfusion or excessive mechanical load, and includes multiple molecular and cellular processes
To understand which miRNA is involved in the process of cardiac remodeling, we used a miRNA microarray approach to identify changes in miRNA expression and determine which miRNA was involved in the process of Angiotensin II (AngII)-induced cardiac remodeling
Among the miRNAs identified in this screen, miR-154-5p expression was confirmed to be significantly increased in the AngII-treated mouse model, suggesting that it might be involved in the development of cardiac remodeling (Figure 1(g))

Summary

Introduction

Cardiac remodeling is an adaptive response to pathophysiological stimuli, such as ischemia/reperfusion or excessive mechanical load, and includes multiple molecular and cellular processes. Cardiac remodeling may serve as a compensatory response; it slowly progresses to a decompensatory effect on heart function [1]. The mechanisms of pathological cardiac remodeling mainly include cardiomyocyte hypertrophy in response to both mechanical and neurohumoral triggers, cardiomyocyte loss mediated by cell death pathways, and fibrosis leading to the accumulation of an excess extracellular matrix [2]. Angiotensin II (AngII), a core component of the renin-angiotensin system (RAS), plays a key role in the onset and development of cardiac remodeling. Two receptors for AngII are expressed in the heart: AT1 and AT2. AT1 receptors have been proposed to mediate most of the pathophysiological effects of AngII, whereas the functions of AT2 receptors remain controversial. Many antihypertensive drugs have been designed to block the AT1 receptor [3]

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