Yin Yang 1 Suppresses Dilated Cardiomyopathy and Cardiac Fibrosis Through Regulation of <i>Bmp7</i> and <i>Ctgf</i>.

Abstract

Pathogenic variations in the lamin gene (<i>LMNA</i>) cause familial dilated cardiomyopathy (DCM). <i>LMNA</i> insufficiency caused by <i>LMNA</i> pathogenic variants is believed to be the basic mechanism underpinning <i>LMNA</i>-related DCM. To assess whether silencing of cardiac <i>Lmna</i> causes DCM and investigate the role of Yin Yang 1 (<i>Yy1</i>) in suppressing <i>Lmna</i> DCM. We developed a <i>Lmna</i> DCM mouse model induced by cardiac-specific <i>Lmna</i> short hairpin RNA. Silencing of cardiac <i>Lmna</i> induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of <i>Yy1</i> suppressed <i>Lmna</i> DCM and cardiac fibrosis by inducing <i>Bmp7</i> expression and preventing upregulation of <i>Ctgf</i>. Knockdown of upregulated <i>Bmp7</i> attenuated the suppressive effect of <i>Yy1</i> on DCM and cardiac fibrosis. However, upregulation of <i>Bmp7</i> alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of <i>Bmp7</i> together with <i>Ctgf</i> silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, upregulation of <i>Yy1</i> regulated <i>Bmp7</i> and <i>Ctgf</i> reporter activities and modulated <i>Bmp7</i> and <i>Ctgf</i> gene expression in cardiomyocytes. Downregulation of <i>Ctgf</i> inhibited TGF-β (transforming growth factor-β)/Smad signaling in DCM hearts. Regulation of both <i>Bmp7</i> and <i>Ctgf</i> further suppressed TGFβ/Smad signaling. In addition, co-modulation of <i>Bmp7</i> and <i>Ctgf</i> reduced CD3+ T cell numbers in DCM hearts. Our findings demonstrate that upregulation of <i>Yy1</i> or co-modulation of <i>Bmp7</i> and <i>Ctgf</i> offer novel therapeutic strategies for the treatment of DCM caused by <i>LMNA</i> insufficiency.