The Role of Atrial Natriuretic Peptide Signalling in Ventricular Conduction System Development and Cardiac Function

Abstract

The presence of a cardiac conduction defect in perinatal life increases the risk of heart failure. Studies have shown that atrial natriuretic peptide (ANP) and its high affinity receptor (NPRA) play a role in the formation of the ventricular conduction system (VCS). However, the specific regulatory mechanism underlying this process remains unknown. While the impact of ANP/NPRA signalling on energy metabolism in noncardiac cells is well-documented, its metabolic effects on the proliferation and differentiation of developing cardiomyocytes and VCS cell development in particular are not known. In this study, histological sections, and primary cultures from E11.5 mouse ventricles were examined to investigate the role of metabolic adaptations in development of VCS cells. Exogenous treatment of E11.5 ventricular cells with ANP revealed a significant increase in lipid droplet accumulation and higher expression of VCS marker Cx40. Furthermore, it was found that ANP/NPRA signalling plays a role in the regulation of metabolic events of embryonic ventricular cells by promoting fatty acid oxidation (FAO). Using specific inhibitors, PPARγ and FAO were identified as critical downstream regulators of ANP-mediated effects on VCS formation. Additional findings revealed that neonatal mice lacking NPRA displayed VCS defects and arrhythmia, which also persisted in adult mice. Furthermore, the cardiac function of NPRA-deficient mice worsened with age, with males being more affected. Overall, this study provides novel insights into the mechanistic understanding of ANP-mediated VCS development through metabolic regulation. It also highlights the impact of age and sex on the cardiac function of NPRA-deficient mice. These findings may contribute to the development of clinical strategies for the treatment of individuals with congenital or acquired heart diseases.