SAT-037 Functional Interplay between Distinct P-TEFb Complexes Following Endothelin or α1-Adrenergic Receptor Activation in Rat Cardiomyocytes

Heart disease is characterized by the remodelling of cardiac tissue following prolonged stress on the heart, such as myocardial infarction and chronic hypertension. The heart initially undergoes hypertrophy of the individual contractile unit, the cardiomyocyte, in order to preserve cardiac function. However, prolonged stress can lead to fibrosis, cardiomyocyte death, and subsequent heart failure. Cardiac remodelling is mediated predominantly through neurohormonal activation of G protein-coupled receptors (GPCRs) expressed by cardiomyocytes and other cell types in the heart. Current therapeutic approaches target implicated GPCRs to slow disease progression by inhibiting signalling pathways leading to remodelling. While this approach benefits a portion of patients, other therapeutic approaches are required to improve disease prognosis (1). A potential target downstream of GPCR activation is the transcription regulator positive transcription elongation factor b (P-TEFb). Hormonal activation of multiple GPCRs, such as the α1-adrenergic receptor (α1AR) by epinephrine or the endothelin receptor (ETR) by endothelin-1, leads to P-TEFb-dependent cardiomyocyte hypertrophy, a hallmark of cardiac remodelling (2). Active P-TEFb is recruited to chromatin to regulate gene expression as a constituent of two complexes, either through interactions with the Super Elongation Complex (SEC) or the bromodomain and extra-terminal protein Brd4. Small molecule inhibition of Brd4 prevents hypertrophy and activation of inflammatory and profibrotic genes in cardiomyocytes (3). On the other hand, the role of the SEC in regulating cardiomyocyte gene expression has not been examined. Furthermore, the signalling mechanisms leading to activation of either complex and subsequent gene expression changes are not known. We hypothesized that activation and interplay between distinct P-TEFb complexes differs following activation of different GPCRs implicated in heart failure. We assessed the role of Brd4 and the SEC downstream of the endogenous ETR and α1AR stimulated with endothelin-1 or phenylephrine, respectively, in primary neonatal rat cardiomyocytes. Although P-TEFb activity is required downstream of both receptors to drive gene expression changes and cardiomyocyte hypertrophy, we find evidence for receptor-specific differences in the functions of the SEC and the Brd4 complex. We are currently investigating signalling mechanisms regulating each complex downstream of the ETR and α1AR. Understanding how mechanisms downstream of various hormones differentially regulate transcription has clinical implications as therapies targeting transcriptional machinery are being explored for heart failure. (1) Wang et al., Circ Res. 2018; 123:716-35 (2) Sano et al., Nat Med. 2002; 8:1310-7 (3) Duan et al., Sci Transl Med; 9(390)

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