Yin Yang 1 Suppresses Dilated Cardiomyopathy and Cardiac Fibrosis Through Regulation of and .

RATIONALE

Pathogenic variations in the lamin gene () cause familial dilated cardiomyopathy (DCM). insufficiency caused by pathogenic variants is believed to be the basic mechanism underpinning -related DCM.

OBJECTIVE

To assess whether silencing of cardiac causes DCM and investigate the role of Yin Yang 1 () in suppressing DCM.

METHODS AND RESULTS

We developed a DCM mouse model induced by cardiac-specific short hairpin RNA. Silencing of cardiac induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of suppressed DCM and cardiac fibrosis by inducing expression and preventing upregulation of . Knockdown of upregulated attenuated the suppressive effect of on DCM and cardiac fibrosis. However, upregulation of alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of together with silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, upregulation of regulated and reporter activities and modulated and gene expression in cardiomyocytes. Downregulation of inhibited TGF-β (transforming growth factor-β)/Smad signaling in DCM hearts. Regulation of both and further suppressed TGFβ/Smad signaling. In addition, co-modulation of and reduced CD3+ T cell numbers in DCM hearts.

CONCLUSIONS

Our findings demonstrate that upregulation of or co-modulation of and offer novel therapeutic strategies for the treatment of DCM caused by insufficiency.