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Targeting MRTF/SRF in CAP2-dependent dilated cardiomyopathy delays disease onset
Yao Xiong, … , Kenneth B. Margulies, Jeffrey Field
Yao Xiong, … , Kenneth B. Margulies, Jeffrey Field
Published February 14, 2019
Citation Information: JCI Insight. 2019;4(6):e124629. https://doi.org/10.1172/jci.insight.124629.
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Research Article Cardiology Therapeutics

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

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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.

Authors

Yao Xiong, Kenneth Bedi, Simon Berritt, Bennette K. Attipoe, Thomas G. Brooks, Kevin Wang, Kenneth B. Margulies, Jeffrey Field

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Figure 3

The SRF pathway is specifically activated in hearts from CAP2-KO mice and associated with MRTFB translocation.

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The SRF pathway is specifically activated in hearts from CAP2-KO mice an...
(A) SRF target genes are activated in hearts but not brains or skeletal muscle from CAP2-KO mice. Expression levels of SRF targets Myl9 and Acta2 were determined in CAP2-KO mice (n = 3); data is presented as mean ± SEM. Three technical triplicates were used in each sample. (B) Relative expression level of Myl9 and cfos in hearts from CAP2-KO mice (n = 5) and age-matched WT mice (n = 5). SRF regulation through 2 pathways. Note the difference in scales from A. Data is presented as mean ± SEM. P value compared with WT mice was based on the Student’s t test. Three technical triplicates were used in each sample. (C) Representative Western blots and quantification showing MRTFB nuclear accumulation in CAP2-KO mice hearts (n = 2). Data is presented as the mean of the values; P value was based on Student’s t test. Western blot of SRF and MRTFA and MRTFB in nuclear and cytoplasmic extracts from mice hearts (n = 2). Right panel shows quantification of the Western blot using ImageJ software. Three technical replicates were used in each sample.

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