G protein-coupled receptor-mediated transcriptional regulation in pathological cardiac remodelling

Pathological cardiac remodelling is an adaptive response to various stressors placed on the heart, such as sustained hypertension or following myocardial infarction. The remodelling attempts to preserve cardiac function and contractility through increased left ventricular wall thickness via a hypertrophic response in cardiomyocytes. At the same time, cardiac fibroblasts are activated and mediate a fibrotic response in damaged areas to maintain structural integrity and aid in wound healing. While initially adaptative, chronic activation of these processes can lead to left ventricle dilation and heart failure, where the heart is no longer able to maintain the necessary cardiac output. This remodelling is predominantly mediated through neurohormonal activation of multiple G protein-coupled receptors (GPCRs), as well as their Gα and Gβγ partner proteins, to elicit intracellular signalling cascades in the different cell types. Currently, the primary therapies are aimed at blocking these receptors. Despite modest clinical success of these therapies, heart failure remains a leading cause of mortality in Canada. Therefore, development of new approaches are required to understand and impact disease progression and improve patient prognosis. GPCR signalling pathways converge on the transcriptional machinery to regulate gene expression changes critical for the development of pathological cardiac remodelling. Due to the integration of multiple pathological signals by the transcriptional machinery, therapies targeting these processes are an attractive prospect that may have greater efficacy than current options. This thesis describes how GPCR signalling pathways alter the activity of the transcriptional machinery to regulate the gene expression changes underlying pathological cardiac remodelling. Herein, we identify the differential activation of Gαs/cAMP/PKA signalling between two GPCRs that drive hypertrophy, the α1-adrenergic receptor and the endothelin-1 receptor, in both primary rat neonatal cardiomyocytes and a heterologous HEK 293 cell system. Furthermore, we demonstrate the implications of the differential signalling between the α1-adrenergic and endothelin-1 receptors on positive transcription elongation factor b (P-TEFb) recruitment mechanisms employed by either receptor to promote cardiomyocyte hypertrophy. Additionally, we demonstrate the regulatory role of an interaction between Gβγ and RNA polymerase II on fibrotic gene expression downstream of the angiotensin II type I receptor in primary rat neonatal cardiac fibroblasts. Overall, this thesis expands our understanding of how GPCR signalling regulates the transcriptional machinery and proposes important considerations for the use and development of therapies for heart failure

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