Upregulation of miR-93 and inhibition of LIMK1 improve ventricular remodeling and alleviate cardiac dysfunction in rats with chronic heart failure by inhibiting RhoA/ROCK signaling pathway activation.

Qian Su,Pengfei Liao,Guizhi Yin,Dong Yu,Fangfang Shen,Peng Zhang,Dandan Li,Zhaodi Wu

doi:10.18632/aging.102272

Abstract

Objective: There are some researches about the role of microRNA (miRNA) in chronic heart failure (CHF) were performed, but the study about miR-93’s function in CHF is scarcely investigated. Thus, we determined to probe into the effects of miR-93 in rats with CHF by targeting LIMK1 through regulating RhoA/ROCK pathway.Results: We found increased LIMK1 and decreased miR-93 in CHF rats, and up-regulation of miR-93 inhibited LIMK1, RhoA and ROCK1 expression in CHF rats. Up-regulation of miR-93 or inhibition of LIMK1 decreased oxidative stress, inflammatory factors, as well as apoptosis-related indicators in CHF rats. LIMK1 was confirmed as a direct target gene of miR-93.Conclusion: Our study provides evidence that upregulated miR-93 and downregulated LIMK1 improve ventricular remodeling and reduce cardiac dysfunction in CHF rats by inhibiting RhoA/ROCK signaling pathway activation.Methods: First, rat models of CHF were established by aortic coarctation, and the rats were injected with miR-93 mimics, LIMK1-siRNA or overexpressed-LIMK1. Then expression of miR-93, LIMK1, RhoA, and ROCK1 expression in myocardial tissues were detected, after which indices of cardiac ultrasound, hemodynamics, and oxidative stress, inflammatory factors, apoptosis-related indicators were detected via a series of assays. Finally, the targeting relationship of miR-93 and LIMK1 was verified.

Highlights

Chronic heart failure (CHF) is a conventional, severe, and disabling but treatable syndrome, and the pharmacological therapy for CHF includes a mixture of neurohormonal antagonists covering an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, and/or aldosterone antagonist [1]
The results showed that the expression of miR-93 in the CHF group was obviously lower than that in the sham group, and the expression levels of LIM domain kinase 1 (LIMK1), RhoA and ROCK1 were dramatically increased
No significant differences were found in expression levels of LIMK1, RhoA and ROCK1 among CHF group, mimics-negative control (NC) group, siRNA-NC group and miR93 mimics + OE-LIMK1 group

Summary

Introduction

Chronic heart failure (CHF) is a conventional, severe, and disabling but treatable syndrome, and the pharmacological therapy for CHF includes a mixture of neurohormonal antagonists covering an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, and/or aldosterone antagonist [1]. CHF remains the final ordinary endpoint of the most of cardiac conditions, anaemia of unascertained origin is frequently presented in CHF patients and leaves an even inferior prognosis [2]. Various factors are related to increased mortality and morbidity in patients with CHF, such as demographic, clinical, and laboratory variables, and its syndrome involves the concurrent activation of multiple neurohormonal systems [3]. Patients with CHF have characteristics of autonomic dysfunction characterized by excessive sympathetic activation and accompanying parasympathetic withdrawal [4]. Patients with CHF with a preserved ejection fraction have descending ventricular relaxation, disordered active relaxation, and/or an increase in ventricular and arterial www.aging-us.com stiffness. Patients with a depressed ejection fraction have a disordered contraction pattern, most of them have diastolic dysfunction [5]. Some microRNAs (miRNAs), such as miR-21, miR-378, and miR-940 are reported to be involved in CHF [6], but researches about function of miR-93 in CHF are hardly discussed, our study was aimed to explore an effective therapeutic mechanism concerning miR-93 for CHF treatment

Methods

Results

Conclusion