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

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.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

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Source: The American Journal of Nursing - Category: Nursing Authors: Tags: Am J Nurs Source Type: research
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Source: Rheumatology International - Category: Rheumatology Source Type: research
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Source: Biomarkers - Category: Research Tags: Biomarkers Source Type: research
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Source: IJC Heart and Vasculature - Category: Cardiology Source Type: research
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Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
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Source: Heart Failure Reviews - Category: Cardiology Source Type: research
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Source: Heart, Lung and Circulation - Category: Cardiology Authors: Source Type: research
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Source: Cardiophile MD - Category: Cardiology Authors: Tags: Cardiology MCQ DM / DNB Cardiology Entrance Featured Source Type: blogs
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Source: PLOS Currents Muscular Dystrophy - Category: Neurology Authors: Source Type: research
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Source: Molecular Medicine Reports - Category: Molecular Biology Tags: Mol Med Rep Source Type: research
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