Browsing by Subject "Mitochondria, Heart"
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Item Novel Roles for BET Bromodomain Protein 4 (BRD4) in Cardiac Physiology and Disease(2020-08-01T05:00:00.000Z) Kim, Soo Young; Munshi, Nikhil; Chiang, Cheng-Ming; Rothermel, Beverly A.; Gupta, Rana K.; Hill, Joseph A.; Gillette, Thomas G.Bromodomain (BRD) protein of the BET (Bromodomain and Extra-Terminal) family are epigenetic reader proteins that have emerged as novel therapeutic targets in cardiovascular disease as well as in a variety of cancers. Small molecule BET inhibitors, such as JQ1, have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet, genetic studies elucidating the biology of BRD proteins in the heart have not been conducted to validate pharmacological findings and unveil potential side effects. Focusing on BRD4, we tested the hypothesis that cardiomyocyte BRD4 drives pathological cardiac remodeling in the setting of disease-related stress. To facilitate these studies, we engineered a cardiomyocyte-specific BRD4 knockout mouse. Using this model, we investigated the role of BRD4 in cardiac physiology and disease. To our surprise, loss of BRD4 protein triggered a spontaneous and progressive decline in myocardial contractile performance, culminating in dilated cardiomyopathy. Transcriptome analysis of BRD4 knockout mouse hearts showed early and specific disruption of genes essential to mitochondrial energy production and homeostasis. Functional analysis of isolated mitochondria confirmed that BRD4 ablation results in specific changes in protein levels and activity of the mitochondrial electron transport chain. Comparative analysis of the JQ1-altered transcriptome suggests that a BRD4-dependent effect of BET inhibition includes changes in transcription of nucleus-encoded mitochondrial genes, raising concerns for cardiotoxicity with potent pharmacological BET inhibition. Furthermore, we tested the roles of BRD4 isoforms, BRD4-L and BRD4-S(a), in cardiomyocyte biology. Isoform-specific knockdown of BRD4 using siRNAs in primary cardiomyocyte culture demonstrated that BRD4-S(a) is required for cardiomyocyte hypertrophy. BRD4-S(a) expression was low in naïve hearts, but it increased significantly in remodeling and failing hearts. Moreover, transgenic over-expression revealed that the BRD4-S(a) isoform is sufficient to induce hypertrophic remodeling and heart failure. In contrast, restoring BRD4-L expression partially rescued systolic dysfunction in animals with a cardiomyocyte specific deletion of BRD4. In conclusion, present study provides evidence that BRD4 regulates cardiomyocyte mitochondrial homeostasis, and that it is required for maintaining normal cardiac function in rodents. Moreover, we demonstrated that the BRD4 short isoform is a driver of pathological cardiac hypertrophy, whereas the long isoform may have a homeostatic role. In aggregate, we have identified novel roles of BRD4 in cardiomyocyte biology, unveiling critical insights - as well as caveats - regarding the therapeutic targeting of BRD proteins in heart failure.