Characterizing The Role Of Atrial Natriuretic Peptide Signalling In The Development Of The Embryonic Ventricular Conduction System
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Ventricular arrhythmias occur as a result of impairment in the conduction of the electrical impulse in the ventricular conduction system (VCS), and present prominently among the complications encountered by patients with congenital heart disease (CHD) and heart failure. Atrial natriuretic peptide (ANP), a paracrine factor produced and stored in the atria, has been shown to be transiently expressed in the ventricular trabeculae of the embryonic heart, which is the main site for the formation of future components of the VCS. We hypothesized that ANP, along with paracrine factors endothelin-1 (ET-1) and neuregulin-1 (NRG-1), interact in a complex cellular signalling network to guide differentiation of non-conduction system cardiac cell types such as cardiac progenitor cells (CPCs) and/or working cardiomyocytes (CMs) toward a VCS cell lineage, thereby promoting formation and development of the VCS. The present study examined the potential impact of ANP on formation of the VCS in the embryonic mouse heart and showed that ANP induces protein and gene expression of important VCS markers such as HCN4 and Cx40 in vitro, through the natriuretic peptide receptor-A (NPR-A)/cGMP/PKG signal transduction pathway. Genetic ablation of NPR-A revealed significant decreases in VCS marker gene expression and defects in Purkinje fiber arborisation. Additional experiments revealed that the NPR-A antagonist A71915 behaves as a competitive antagonist at a specific concentration in E11.5 mouse ventricular cells. Lastly, this study provides evidence that the ANP, ET-1, and NRG-1 signalling systems interact in a cooperative manner to induce development of the VCS in the embryonic mouse heart. Results from this thesis provide new insights into the molecular mechanisms that guide development of the VCS, specifically the potential role of ANP and the complex interplay between ANP, ET-1, and/or NRG-1 signalling pathways in the formation of the VCS. Collectively, results from these studies may facilitate the development of clinical strategies to aid in the treatment of children and patients born with arrhythmia-associated CHDs.