Role of the PRC2-Six1-miR-25 signaling axis in heart failure

Jae Gyun Oh,Seung Pil Jang,Jimeen Yoo,Min-Ah Lee,Seung Hee Lee,Taejoong Lim,Eden Jeong,Changwon Kho,Hyun Kook,Roger J Hajjar,Woo Jin Park,Dongtak Jeong

doi:10.1016/j.yjmcc.2019.01.017

Abstract

The reduced expression of cardiac sarco-endoplasmic reticulum Ca2+ ATPase (SERCA2a) is a hallmark of heart failure. We previously showed that miR-25 is a crucial transcriptional regulator of SERCA2a in the heart. However, the precise mechanism of cardiac miR-25 regulation is largely unknown. Literatures suggested that miR-25 is regulated by the transcriptional co-factor, sine oculis homeobox homolog 1 (Six1), which in turn is epigenetically regulated by polycomb repressive complex 2 (PRC 2) in cardiac progenitor cells. Therefore, we aimed to investigate whether Six1 and PRC2 are indeed involved in the regulation of the miR-25 level in the setting of heart failure. Six1 was up-regulated in the failing hearts of humans and mice. Overexpression of Six1 led to adverse cardiac remodeling, whereas knock-down of Six1 attenuated pressure overload-induced cardiac dysfunction. The adverse effects of Six1 were ameliorated by knock-down of miR-25. The epigenetic repression on the Six1 promoter by PRC2 was significantly reduced in failing hearts. Epigenetic repression of Six1 is relieved through a reduction of PRC2 activity in heart failure. Six1 up-regulates miR-25, which is followed by reduction of cardiac SERCA2a expression. Collectively, these data showed that the PRC2-Six1-miR-25 signaling axis is involved in heart failure. Our finding introduces new insight into potential treatments of heart failure.

Highlights

Heart failure (HF) is a leading cause of mortality and morbidity worldwide [1]
sine oculis homeobox homolog 1 (Six1) is up-regulated in human and mouse failing hearts, and this up-regulation coincides with the up-regulation of miR-25 and the down-regulation of sarco-endoplasmic reticulum Ca2+ ATPase (SERCA2a), implying a potential role of Six1 in HF
HF was induced in mice by applying transverse aortic constriction (TAC) for 8 weeks, and AAV9 siSix1 or control virus, AAV9 Cont, was injected via the tail vein

Summary

Introduction

Heart failure (HF) is a leading cause of mortality and morbidity worldwide [1]. In the US, cardiovascular disease accounts for almost one in every three deaths, making it a primary health concern [1]. Modulation of SERCA2a activity and expression has proven effective in improving key parameters of HF [3]

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