1. Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset.
- Author
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Xiong Y, Bedi K, Berritt S, Attipoe BK, Brooks TG, Wang K, Margulies KB, and Field J
- Subjects
- Animals, Cardiomyopathy, Dilated genetics, Cardiomyopathy, Dilated mortality, Cardiomyopathy, Dilated pathology, Carrier Proteins metabolism, Cytoskeleton drug effects, Cytoskeleton pathology, Disease Models, Animal, Female, Fetus, Heart drug effects, Heart embryology, Humans, Longevity drug effects, Male, Mice, Myocardium cytology, Myocardium metabolism, Myocardium pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, RNA-Seq, Serum Response Factor metabolism, Signal Transduction drug effects, Signal Transduction genetics, Time Factors, Transcription Factors metabolism, Anilides administration & dosage, Benzamides administration & dosage, Cardiomyopathy, Dilated drug therapy, Carrier Proteins genetics, Gene Expression Regulation, Developmental drug effects, Serum Response Factor antagonists & inhibitors
- Abstract
About one-third of dilated cardiomyopathy (DCM) cases are caused by mutations in sarcomere or cytoskeletal proteins. However, treating the cytoskeleton directly is not possible because drugs that bind to actin are not well tolerated. Mutations in the actin binding protein CAP2 can cause DCM and KO mice, either whole body (CAP2-KO) or cardiomyocyte-specific KOs (CAP2-CKO) develop DCM with cardiac conduction disease. RNA sequencing analysis of CAP2-KO hearts and isolated cardiomyocytes revealed overactivation of fetal genes, including serum response factor-regulated (SRF-regulated) genes such as Myl9 and Acta2 prior to the emergence of cardiac disease. To test if we could treat CAP2-KO mice, we synthesized and tested the SRF inhibitor CCG-1423-8u. CCG-1423-8u reduced expression of the SRF targets Myl9 and Acta2, as well as the biomarker of heart failure, Nppa. The median survival of CAP2-CKO mice was 98 days, while CCG-1423-8u-treated CKO mice survived for 116 days and also maintained normal cardiac function longer. These results suggest that some forms of sudden cardiac death and cardiac conduction disease are under cytoskeletal stress and that inhibiting signaling through SRF may benefit DCM by reducing cytoskeletal stress.
- Published
- 2019
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