Zinc-finger protein 418 overexpression protects against cardiac hypertrophy and fibrosis.

Liming Pan,Zirui Huang,Zhilin Zhu,Lin Teng,Chunli Xu,Mengting Sheng,Chen Gu,Ling He,Cai Yi,Junming Li,Michael Bader

doi:10.1371/journal.pone.0186635

Abstract

BackgroundThis study aimed to investigated the effect and mechanism of zinc-finger protein 418 (ZNF418) on cardiac hypertrophy caused by aortic banding (AB), phenylephrine (PE) or angiotensin II (Ang II) in vivo and in vitro.MethodsThe expression of ZNF418 in hearts of patients with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) and AB-induced cardiac hypertrophy mice, as well as in Ang II- or PE-induced hypertrophic primary cardiomyocytes was detected by western blotting. Then, the expression of ZNF418 was up-regulated or down-regulated in AB-induced cardiac hypertrophy mice and Ang II -induced hypertrophic primary cardiomyocytes. The hypertrophic responses and fibrosis were evaluated by echocardiography and histological analysis. The mRNA levels of hypertrophy markers and fibrotic markers were detected by RT-qPCR. Furthermore, the phosphorylation and total levels of c-Jun were measured by western blotting.ResultsZNF418 was markedly down-regulated in hearts of cardiac hypertrophy and hypertrophic primary cardiomyocytes. Down-regulated ZNF418 exacerbated the myocyte size and fibrosis, moreover increased the mRNA levels of ANP, BNP, β-MHC, MCIP1.4, collagen 1a, collagen III, MMP-2 and fibronection in hearts of AB-treated ZNF418 knockout mice or Ang II-treated cardiomyocytes with AdshZNF418. Conversely, these hypertrophic responses were reduced in the ZNF418 transgenic (TG) mice treated by AB and the AdZNF418-transfected primary cardiomyocytes treated by Ang II. Additionally, the deficiency of ZNF418 enhanced the phosphorylation level of c-jun, and overexpression of ZNF418 suppressed the phosphorylation level of c-jun in vivo and in vitro.ConclusionZNF418 maybe attenuate hypertrophic responses by inhibiting the activity of c-jun/AP-1.

Highlights

Cardiac hypertrophy is a common pathological change in patients with progressive cardiac function failure, which can be caused by some intrinsic or extrinsic factors, including familial hypertrophic cardiomyopathy (HCM) or arterial hypertension and dilated cardiomyopathy (DCM) [1,2]
Effect of zinc-finger protein 418 (ZNF418) on cardiac hypertrophy reduced in the ZNF418 transgenic (TG) mice treated by aortic banding (AB) and the AdZNF418-transfected primary cardiomyocytes treated by angiotensin II (Ang II)
After treatment with either Ang II or PE for 48 h, the expression level of ZNF418 was reduced by 47% (Ang II) and 71% (PE) compared with primary cardiomyocytes treated with phosphate buffered saline (PBS) (P < 0.05, Fig 1C)

Summary

Introduction

Cardiac hypertrophy is a common pathological change in patients with progressive cardiac function failure, which can be caused by some intrinsic or extrinsic factors, including familial hypertrophic cardiomyopathy (HCM) or arterial hypertension and dilated cardiomyopathy (DCM) [1,2]. Previous studies have demonstrated that a number of signal transduction pathways are implicated in the development of cardiac hypertrophy, including mitogen-activated protein kinase (MAPK) pathway, phosphoinositide 3-kinase (PI3K)/Akt pathway, protein kinase C (PKC) pathway [8,9,10]. These intracellular signaling cascades can regulate the expression levels of ANP, BNP, and β-MHC through activating various transcriptional regulatory proteins such as activator protein-1 (AP-1), thereby exacerbating cardiac hypertrophy [7,11]. This study aimed to investigated the effect and mechanism of zinc-finger protein 418 (ZNF418) on cardiac hypertrophy caused by aortic banding (AB), phenylephrine (PE) or angiotensin II (Ang II) in vivo and in vitro

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