Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset

About one third of dilated cardiomyopathy (DCM) cases are caused by mutations in sarcomere or cytoskeletal proteins. Yet 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 knockout mice, either whole body (CAP2 KO) or cardiomyocyte specific knockouts (CAP2 CKO), develop DCM with cardiac conduction disease. RNA-seq analysis of CAP2 KO hearts and isolated cardiomyocytes revealed over-activation of fetal genes including serum response factor (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 maintain 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. Overall design: Heart mRNA profiles of 86-week old wild type (WT), CAP2-/- mice 3 replicates each for experiment A, and in experiment B, 5 replicates of 13-week old loxp mice and 4 replicates of L/L,Myh6-cre+ mice, were generated by deep sequencing, in triplicate, using Illumina GAIIx. A 5th L/L,Myh6-cre+ had originally failed sequencing and was excluded from the study, but has since been resequenced and is included (sample KO_m_1623). The processed data of experiment B normalized read counts does not include this last sample as it was not part of the study.