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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 1

Genes and pathways altered in whole body CAP2-KO mice and CAP2-CKO mice.

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Genes and pathways altered in whole body CAP2-KO mice and CAP2-CKO mice....
For KO mice and its controls, RNA was isolated from female WT mice (n = 3) and mutant CAP2 KO hearts (n = 3), ages ~86 weeks old. For CKO mice, RNA was isolated from male (n = 2) and female (n = 3) rescued mice and male (n = 1) and female (n = 3) CAP2-CKO mice hearts, ages ~13 weeks old. The samples were subjected to RNA-seq analysis, and genes were ranked by differential expression P values as determined by the limma-voom software. Pathway analysis by Ingenuity Pathway Analysis (IPA) software was performed on the list of all genes that were differentially expressed genes with FDR < 0.2 and fold change at least 1.2 in both KO and CKO experiments. (A) Top 50 altered genes in hearts from CAP2 KO mice (n = 3) compared with WT (n = 3) (left) and CAP2-CKO mice (n = 4) compared with age-matched rescued mice (n = 5) (right). (B) The RNA-seq analysis pipeline used in this study. (C) The overlap genes with altered expression levels in both CAP2 KO and CKO mice. (D) Regulators analysis shows serum responsive factor (SRF), TGFβ, and TNF signaling were significantly activated; red means predicted activation by IPA software.

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ISSN 2379-3708

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