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

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