| First Author | Oh JG | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 129 |
| Pages | 58-68 | PubMed ID | 30771307 |
| Mgi Jnum | J:276080 | Mgi Id | MGI:6305030 |
| Doi | 10.1016/j.yjmcc.2019.01.017 | Citation | Oh JG, et al. (2019) Role of the PRC2-Six1-miR-25 signaling axis in heart failure. J Mol Cell Cardiol 129:58-68 |
| abstractText | The reduced expression of cardiac sarco-endoplasmic reticulum Ca(2+) 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. |
