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

2019; Elsevier BV; Volume: 129; Linguagem: Inglês

10.1016/j.yjmcc.2019.01.017

1095-8584

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,

Multilevel Inverters and Converters

Highlights•Six1 is up-regulated in failing hearts.•Overexpression of Six1 leads to cardiac abnormalities in vitro and in vivo.•In cardiac stress conditions, Six1 directly binds to the MCM7 promoter, inducing an elevation of miR-25, which in turn reduces SERCA2a.•In failing hearts, Six1 is epigenetically regulated through the PRC2 complex across species.AbstractThe 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.