Central Role of Cystathionine γ-Lyase in the Regulation of Cardiac Functions

Abstract

Cardiovascular diseases have been the leading cause of global mortality and morbidity, estimating to kill 18 million people per year. Cardiomyopathy (CM), a disease that affects the myocardium, is considered one of the main drivers. Affected individuals could face heart failure and sudden cardiac deaths due to impaired contractility of the heart. As the underlying causes for CMs remained unknown, there is no cure for this disease and there is a growing interest in discovering therapeutic interventions. Hydrogen sulfide (H2S) is a gasotransmitter that is mainly produced by the cystathionine γ-lyase (CSE) enzyme in the heart. Previous research from our lab emphasised the importance of CSE in cardiovascular adaptations during pregnancy but its physiological effects on age-related changes remains unexplored. The aim of this project was to investigate the effects of global CSE deletion on cardiac function, structure, cellular dynamics and molecular pathways using a transgenic murine model. The longitudinal study revealed that disruption in the CSE/H2S pathway caused agedependent systolic and diastolic dysfunction preceding structural abnormalities using echocardiography. This includes a significant reduction in ejection fraction, increased cardiac volumes, elevated myocardial performance index, and prolonged isovolumetric relaxation time, indicative of compromised contractility and myocardial stiffening. Given the pivotal role of mitochondria in cellular energetics, such functional alterations may result from mitochondrial dysfunction, including reductions in biogenesis and bioenergetics due to loss of CSE. Subsequently, reduced ATP produced is due to electron transport chain inefficiencies. Furthermore, perturbations in mitochondrial dynamics were evident, characterised by reduced fission, fusion and mitophagy in CSE-/- mice. At the molecular level, dysregulated calcium signalling was observed, accompanied by upregulation of genes associated with hypertrophy and inflammation, at the onset of the disease process. In conclusion, proper regulation of the CSE/H2S pathway is essential in maintaining normal cardiovascular functions even under non-energy demanding, resting conditions.