Regulation of Bmp7 and Ctgf Suppresses Dilated Cardiomyopathy and Cardiac Fibrosis

Introduction: Cardiac Lmna insufficiency causes dilated cardiomyopathy (DCM) coupled with cardiac fibrosis and inflammation. TGFβ family members are key mediators for cardiac performance, cardiac fibrosis and inflammation. However, how TGFβ family members are regulated in heart is unknown. Hypothesis: Modulation of downstream pathways could be served as a therapeutic strategy. Methods and Results: We demonstrate that regulation of Bmp7 and Ctgf suppresses Lmna DCM and cardiac fibrosis. Upregulation of Bmp7 alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of Bmp7 together with Ctgf silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, downregulation of Ctgf inhibited TGFβ/Smad signaling pathway in DCM hearts. Co-modulation of Bmp7 and Ctgf reduced infiltration of T cells in hearts. A screen of cardiac related factors identified Yy1 enhanced Bmp7 promoter activity and prevent the upregulation of Ctgf promoter activity. Yy1 suppressed Lmna DCM by inducing Bmp7 expression and reduced Ctgf upregulation in cardiomyocytes. Importantly, knockdown of upregulated Bmp7 attenuated the suppressive effect of Yy1 on DCM and cardiac fibrosis. Conclusions: Our findings demonstrate that DCM caused by LMNA insufficiency can be treated with co-modulation of Bmp7 and Ctgf .