Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 9, Pages 4740-4758Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI135922
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Funding
- NIH, National Heart, Lung, and Blood Institute [NHLBI R01-HL088498, 1R01-HL132401, R01-HL151737, S10-OD018135]
- Leducq Foundation [14 CVD 03]
- National Institute on Aging, NIH [R21-AG060413-01]
- American Heart Association [19POST34410032]
- Ewing Halsell Foundation
- George and Mary Josephine Hamman Foundation
- TexGen Fund from the Greater Houston Community Foundation
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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 chromatinassociated 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.
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