Hydrogen sulfide (H2S) as a regulator of myocardial redox state and the redox-sensitive regulation of cystathionine γ-lyase (CSE)

Thesis

In advanced stages, cardiac disease causes millions of deaths each year. Superoxide anions (O₂^.-) and their derivative peroxynitrite (ONOO^-) contribute to cardiac disease pathogenesis, yet strategies to reduces these reactive oxygen species through antioxidants in large scale clinical trials have largely been unsuccessful. Better understanding of pathways regulating enzymatic sources of O₂^.- like NADPH oxidases, uncoupled nitric oxide synthases (NOSs) and mitochondrial oxidases are required to regulate myocardial oxidative stress in patients with advanced stages of cardiac disease. Hydrogen sulfide (H2S) is a gaseous signalling molecule generated by transsulfuration pathway enzymes cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST). H₂S regulates oxidative stress in animal models and shows promise for cardiovascular therapeutic strategy. This thesis investigates whether H₂S/CSE biology is related to human myocardial redox state in a cohort of individuals with advanced cardiac disease (Oxford Heart, Fat, Vessels Cohort; Ox-HVF). Individuals with varying levels of myocardial oxidative stress and function were extensively phenotyped for H₂S biology. Individuals with high myocardial oxidative stress from NADPH oxidases and NOSs were found to have high expression of myocardial CSE. To examine first the positive association with NADPH oxidase activity, CSE expression was examined after myocardial oxidative injury and CSE was found to be redox-sensitive. Furthermore, direct effects of two exogenous H₂S donors (NaHS and GYY4137) demonstrated a direct regulation of O₂^.- from NOSs in myocardium from individuals with advanced cardiac disease, further supporting H₂S’s direct role in the regulation of NOS biology. Finally, identification of a SNP in CSE further demonstrated CSE’s causal role in the regulation of O2.- generation from mitochondrial oxidases. Taken together, we demonstrate for the first time that H₂S and CSE biology are linked to human myocardial redox state and have a causal role in redox regulation in the human heart. These findings suggest H₂S/CSE biology are important endogenous regulators of myocardial redox state in humans and continued exploration of these pathways may develop novel therapeutic strategies against myocardial oxidative stress in cardiac disease.

Authors: Tarun, A

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: cystathionine γ-lyase; oxidative stress; myocardium; hydrogen sulfide
• Subjects: Myocardial redox state; Cardiovascular disease; Hydrogen sulfide biology