Differential Activation of P-TEFb Complexes in the Development of Cardiomyocyte Hypertrophy following Activation of Distinct G Protein-Coupled Receptors

Pathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and is accompa-nied by large-scale changes in cardiomyocyte gene expression. These transcriptional changes require activity of positive transcription elongation factor beta (P-TEF beta), which is recruited to target genes by the bromodomain protein Brd4 or the super elonga-tion complex (SEC). Here, we describe GPCR-specific regulation of these P-TEF beta com-plexes and a novel mechanism for activating Brd4 in primary neonatal rat cardiomy-ocytes. The SEC was required for the hypertrophic response downstream of either the alpha 1-adrenergic receptor (alpha 1-AR) or the endothelin receptor (ETR). In contrast, Brd4 inhibition selectively impaired the alpha 1-AR response. This was corroborated by the finding that the activation of alpha 1-AR, but not ETR, increased Brd4 occupancy at promoters and superenhancers of hypertrophic genes. Transcriptome analysis demon-strated that the activation of both receptors initiated similar gene expression pro-grams, but that Brd4 inhibition attenuated hypertrophic genes more robustly following alpha 1-AR activation. Finally, we show that protein kinase A (PKA) is re-quired for alpha 1-AR stimulation of Brd4 chromatin occupancy. The differential role of the Brd4/P-TEFb complex in response to distinct GPCR pathways has potential clinical implications, as therapies targeting this complex are currently being ex-plored for heart failure.