Chia Yee Tan1,2, Jing Xuan Wong1,2, Pui Shi Chan1,2, Hansen Tan1,2, Dan Liao1,2, Weiming Chen1,2, Lek Wen Tan3, Matthew Ackers-Johnson2,3, Hiroko Wakimoto4, Jonathan G Seidman4, Christine E Seidman4, Ida Gjervold Lunde5, Feng Zhu6, Qidong Hu7, Jinsong Bian8, Jiong-Wei Wang2,9,10, Roger S Foo2,3, Jianming Jiang1,2. 1. From the Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (C.Y.T., J.X.W., P.S.C., H.T., D.L., W.C., J.J.). 2. Cardiovascular Research Institute, National University Health System, Centre for Translational Medicine, Singapore (C.Y.T., J.X.W., P.S.C., H.T., D.L., W.C., M.A.-J., J.W.W., R.S.F., J.J.). 3. Genome Institute of Singapore, A*STAR (L.W.T., M.A.-J., R.S.F.). 4. Genetics, Harvard Medical School, Boston, MA (H.W., J.G.S., C.E.S.). 5. Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Norway (I.G.L.). 6. School of Computer, Jiangsu University of Science and Technology, Zhenjiang, P.R China (F.Z.). 7. Anatomy (Q.H.), Yong Loo Lin School of Medicine, National University of Singapore. 8. Pharmacology (J.B.), Yong Loo Lin School of Medicine, National University of Singapore. 9. Physiology (J.-W.W.), Yong Loo Lin School of Medicine, National University of Singapore. 10. Surgery (J.-W.W.), Yong Loo Lin School of Medicine, National University of Singapore.
Abstract
RATIONALE: Pathogenic variations in the lamin gene (LMNA) cause familial dilated cardiomyopathy (DCM). LMNA insufficiency caused by LMNA pathogenic variants is believed to be the basic mechanism underpinning LMNA-related DCM. OBJECTIVE: To assess whether silencing of cardiac Lmna causes DCM and investigate the role of Yin Yang 1 (Yy1) in suppressing Lmna DCM. METHODS AND RESULTS: We developed a Lmna DCM mouse model induced by cardiac-specific Lmna short hairpin RNA. Silencing of cardiac Lmna induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of Yy1 suppressed Lmna DCM and cardiac fibrosis by inducing Bmp7 expression and preventing upregulation of Ctgf. Knockdown of upregulated Bmp7 attenuated the suppressive effect of Yy1 on DCM and cardiac fibrosis. However, 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, upregulation of Yy1 regulated Bmp7 and Ctgf reporter activities and modulated Bmp7 and Ctgf gene expression in cardiomyocytes. Downregulation of Ctgf inhibited TGF-β (transforming growth factor-β)/Smad signaling in DCM hearts. Regulation of both Bmp7 and Ctgf further suppressed TGFβ/Smad signaling. In addition, co-modulation of Bmp7 and Ctgf reduced CD3+ T cell numbers in DCM hearts. CONCLUSIONS: Our findings demonstrate that upregulation of Yy1 or co-modulation of Bmp7 and Ctgf offer novel therapeutic strategies for the treatment of DCM caused by LMNA insufficiency.
RATIONALE: Pathogenic variations in the lamin gene (LMNA) cause familial dilated cardiomyopathy (DCM). LMNA insufficiency caused by LMNA pathogenic variants is believed to be the basic mechanism underpinning LMNA-related DCM. OBJECTIVE: To assess whether silencing of cardiac Lmna causes DCM and investigate the role of Yin Yang 1 (Yy1) in suppressing Lmna DCM. METHODS AND RESULTS: We developed a Lmna DCMmouse model induced by cardiac-specific Lmna short hairpin RNA. Silencing of cardiac Lmna induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of Yy1 suppressed Lmna DCM and cardiac fibrosis by inducing Bmp7 expression and preventing upregulation of Ctgf. Knockdown of upregulated Bmp7 attenuated the suppressive effect of Yy1 on DCM and cardiac fibrosis. However, 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, upregulation of Yy1 regulated Bmp7 and Ctgf reporter activities and modulated Bmp7 and Ctgf gene expression in cardiomyocytes. Downregulation of Ctgf inhibited TGF-β (transforming growth factor-β)/Smad signaling in DCM hearts. Regulation of both Bmp7 and Ctgf further suppressed TGFβ/Smad signaling. In addition, co-modulation of Bmp7 and Ctgf reduced CD3+ T cell numbers in DCM hearts. CONCLUSIONS: Our findings demonstrate that upregulation of Yy1 or co-modulation of Bmp7 and Ctgf offer novel therapeutic strategies for the treatment of DCM caused by LMNA insufficiency.
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