<P><B>Abstract</B></P> <P>The reduced expression of cardiac sarco-endoplasmic reticulum Ca<SUP>2+</SUP> ATPase (SERCA2a) is a hallmark of heart failure. We previously showed that miR-25 is a crucial transcrip...
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https://www.riss.kr/link?id=A107447417
2019
-
Heart failure ; SERCA2a ; miRNA-25 ; Six1 ; PRC2 ; Epigenetics
SCI,SCIE,SCOPUS
학술저널
58-68(11쪽)
0
상세조회0
다운로드다국어 초록 (Multilingual Abstract)
<P><B>Abstract</B></P> <P>The reduced expression of cardiac sarco-endoplasmic reticulum Ca<SUP>2+</SUP> ATPase (SERCA2a) is a hallmark of heart failure. We previously showed that miR-25 is a crucial transcrip...
<P><B>Abstract</B></P> <P>The reduced expression of cardiac sarco-endoplasmic reticulum Ca<SUP>2+</SUP> 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 <I>Six1</I> 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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Six1 is up-regulated in failing hearts. </LI> <LI> Overexpression of Six1 leads to cardiac abnormalities in vitro and in vivo. </LI> <LI> In cardiac stress conditions, Six1 directly binds to the <I>MCM7</I> promoter, inducing an elevation of miR-25, which in turn reduces SERCA2a. </LI> <LI> In failing hearts, Six1 is epigenetically regulated through the PRC2 complex across species. </LI> </UL> </P>