Differential activation of P-TEFb complexes in the development of cardiomyocyte hypertrophy following activation of distinct GPCRs

Abstract

<jats:title>Abstract</jats:title><jats:p>Pathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and is accompanied by large-scale changes in cardiomyocyte gene expression. These transcriptional changes require activity of positive transcription elongation factor b (P-TEFb), which is recruited to target genes by the bromodomain protein Brd4 or the <jats:italic>S</jats:italic>uper <jats:italic>E</jats:italic>longation <jats:italic>C</jats:italic>omplex (SEC). Here we describe GPCR-specific regulation of these P-TEFb complexes and a novel mechanism for activating Brd4 in primary neonatal rat cardiomyocytes. The SEC was required for the hypertrophic response downstream of either the α<jats:sub>1</jats:sub>-adrenergic receptor (α<jats:sub>1</jats:sub>-AR) or the endothelin receptor (ETR). In contrast, Brd4 inhibition selectively impaired the α<jats:sub>1</jats:sub>-AR response. This was corroborated by the finding that activation of α<jats:sub>1</jats:sub>-AR, but not ETR, increased Brd4 occupancy at promoters and super enhancers of hypertrophic genes. Transcriptome analysis demonstrated that activation of both receptors initiated similar gene expression programs, but that Brd4 inhibition attenuated hypertrophic genes more robustly following α<jats:sub>1</jats:sub>-AR activation. Finally, we show that protein kinase A (PKA) is required for α<jats:sub>1</jats:sub>-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 explored for heart failure.</jats:p>