BET bromodomain inhibition attenuates cardiac phenotype in myocyte-specific lamin A/C–deficient mice
Gaelle Auguste, Leila Rouhi, Scot J. Matkovich, Cristian Coarfa, Matthew J. Robertson, Grazyna Czernuszewicz, Priyatansh Gurha, Ali J. Marian
Gaelle Auguste, Leila Rouhi, Scot J. Matkovich, Cristian Coarfa, Matthew J. Robertson, Grazyna Czernuszewicz, Priyatansh Gurha, Ali J. Marian
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Research Article Cardiology

BET bromodomain inhibition attenuates cardiac phenotype in myocyte-specific lamin A/C–deficient mice

Abstract

Mutation in the LMNA gene, encoding lamin A/C, causes a diverse group of diseases called laminopathies. Cardiac involvement is the major cause of death and manifests as dilated cardiomyopathy, heart failure, arrhythmias, and sudden death. There is no specific therapy for LMNA-associated cardiomyopathy. We report that deletion of Lmna in cardiomyocytes in mice leads to severe cardiac dysfunction, conduction defect, ventricular arrhythmias, fibrosis, apoptosis, and premature death within 4 weeks. The phenotype is similar to LMNA-associated cardiomyopathy in humans. RNA sequencing, performed before the onset of cardiac dysfunction, led to identification of 2338 differentially expressed genes (DEGs) in Lmna-deleted cardiomyocytes. DEGs predicted activation of bromodomain-containing protein 4 (BRD4), a regulator of chromatin-associated proteins and transcription factors, which was confirmed by complementary approaches, including chromatin immunoprecipitation sequencing. Daily injection of JQ1, a specific BET bromodomain inhibitor, partially reversed the DEGs, including those encoding secretome; improved cardiac function; abrogated cardiac arrhythmias, fibrosis, and apoptosis; and prolonged the median survival time 2-fold in the myocyte-specific Lmna-deleted mice. The findings highlight the important role of LMNA in cardiomyocytes and identify BET bromodomain inhibition as a potential therapeutic target in LMNA-associated cardiomyopathy, for which there is no specific effective therapy.

Authors

Gaelle Auguste, Leila Rouhi, Scot J. Matkovich, Cristian Coarfa, Matthew J. Robertson, Grazyna Czernuszewicz, Priyatansh Gurha, Ali J. Marian

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Figure 8

Phenotypic effects of BET bromodomain protein inhibition in Myh6-Cre LmnaF/F mice.

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Phenotypic effects of BET bromodomain protein inhibition in Myh6-Cre Lmn...
(A) Kaplan-Meier survival curves in the untreated (black line; n = 34), vehicle-treated (yellow line; n = 12), and JQ1-treated WT (orange line; n = 14), as well as untreated (red line; n = 28), vehicle-treated (blue line; n = 14), and JQ1-treated Myh6-Cre LmnaF/F (green line; n = 11), mice. (B) Selected echocardiographic parameters after 1 week of treatment in 3-week-old untreated (black dots; n = 12), vehicle-treated (yellow dots; n = 10), and JQ1-treated WT (orange dots; n = 11), as well as untreated (red dots; n = 16), vehicle-treated (blue dots; n = 11), and JQ1-treated (green dots; n = 22) Myh6-Cre LmnaF/F, mice. P values shown were obtained using 2-way ANOVA and Bonferroni’s post hoc test for comparisons; *P < 0.05, †P < 0.01, #P < 0.001, ‡P < 0.0001. PI, P value for interaction; PG, P value for genotype, PRx, P value for treatment effect. (C) Expression levels of known markers of cardiac dysfunction, quantified by RT-qPCR, after 1 week of treatment in 3-week-old untreated (black dots; n = 4) and JQ1-treated WT (orange dots; n = 5) mice, as well as untreated (red dots; n = 6) and JQ1-treated (green dots; n = 8) Myh6-Cre LmnaF/F mice. Because untreated and vehicle-treated mice were indistinguishable, only untreated and JQ1-treated mice were analyzed. P values shown were obtained with ordinary 1-way ANOVA or Kruskal-Wallis; *P < 0.05, †P < 0.01, #P < 0.001, ‡P < 0.0001.