Up-regulation of miR-195 contributes to cardiac hypertrophy-induced arrhythmia by targeting calcium and potassium channels.

Lina Xuan,Chao Yang,Yanmeng Zhu,Lei Jiao,Ying Zhang,Baofeng Yang,Qingqi Li,Lihua Sun,Shengjie Wang,Yunqi Liu,Hua Yang

doi:10.1111/jcmm.15431

Lina Xuan, Chao Yang + Show 9 more

Open Access

https://doi.org/10.1111/jcmm.15431

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Abstract

Previous studies have confirmed that miR‐195 expression is increased in cardiac hypertrophy, and the bioinformatics website predicted by Targetscan software shows that miR‐195 can directly target CACNB1, KCNJ2 and KCND3 to regulate Cavβ1, Kir2.1 and Kv4.3 proteins expression. The purpose of this study is to confirm the role of miR‐195 in arrhythmia caused by cardiac hypertrophy. The protein levels of Cavβ1, Kir2.1 and Kv4.3 in myocardium of HF mice were decreased. After miR‐195 was overexpressed in neonatal mice cardiomyocytes, the expression of ANP, BNP and β‐MHC was up‐regulated, and miR‐195 inhibitor reversed this phenomenon. Overexpression of miR‐195 reduced the estimated cardiac function of EF% and FS% in wild‐type (WT) mice. Transmission electron microscopy showed that the ultrastructure of cardiac tissues was damaged after miR‐195 overexpression by lentivirus in mice. miR‐195 overexpression increased the likelihood of arrhythmia induction and duration of arrhythmia in WT mice. Lenti‐miR‐195 inhibitor carried by lentivirus can reverse the decreased EF% and FS%, the increased incidence of arrhythmia and prolonged duration of arrhythmia induced by TAC in mice. After miR‐195 treatment, the protein expressions of Cavβ1, Kir2.1 and Kv4.3 were decreased in mice. The results were consistent at animal and cellular levels, respectively. Luciferase assay results showed that miR‐195 may directly target CACNB1, KCNJ2 and KCND3 to regulate the expression of Cavβ1, Kir2.1 and Kv4.3 proteins. MiR‐195 is involved in arrhythmia caused by cardiac hypertrophy by inhibiting Cavβ1, Kir2.1 and Kv4.3.

Highlights

Cardiac hypertrophy can trigger atrial and ventricular arrhythmias, increase the risk of morbidity and mortality, and lead to sudden cardiac death in patients.[1,2] Long-term or excessive stress load may lead to a transition from physiological hypertrophy to pathological hypertrophy, and eventually lead to heart failure (HF).[3]
Hypertrophy induced by Transverse Aortic Constriction (TAC) (Figure 1F, ***P < .001 vs. Sham), Kir2.1 were significantly decreased in myocardium of cardiac hypertrophy induced by TAC (Figure 1G, *P < .05 vs. Sham), the protein expression of Kv4.3 was significantly decreased in myocardium of cardiac hypertrophy induced by TAC (Figure 1H, *P < .05 vs. Sham)
Our results showed that compared with the negative control (NC) group, the probability of arrhythmia induction was significantly increased in the lenti-miR-195 injection group, and the duration of arrhythmia was significantly prolonged (Figure 2E, *P < .05 vs. NC)

Summary

Introduction

Cardiac hypertrophy can trigger atrial and ventricular arrhythmias, increase the risk of morbidity and mortality, and lead to sudden cardiac death in patients.[1,2] Long-term or excessive stress load may lead to a transition from physiological hypertrophy to pathological hypertrophy, and eventually lead to heart failure (HF).[3]. In cardiac hypertrophy and HF models, K+ and Ca2+ currents are down-regulated and APD is prolonged, which showed significant electrophysiological remodelling. The Ito and IK1 are central regulators of arrhythmia and may be promising targets for anti-arrhythmic approaches. The exact mechanisms regulating the decreased potassium and calcium channels in hypertrophy need further study

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