Abstract
Cystathionine γ-lyase is a key enzyme in the transsulfuration pathway responsible for endogenous hydrogen sulfide production in the cardiovascular system. As the third gaseous signaling molecule, hydrogen sulfide plays crucial roles in maintaining vascular homeostasis, regulating vasodilation, and protecting against ischemia-reperfusion injury. This review comprehensively analyzes the regulatory mechanisms governing cystathionine γ-lyase expression under various physiological and pathological conditions. Exogenous hydrogen sulfide exhibits concentration-dependent bidirectional regulation of cystathionine γ-lyase expression, with lower concentrations (10-80 μM) suppressing cystathionine γ-lyase through feedback inhibition, while higher concentrations (120-160 μM) upregulating its expression as a protective response. Hydrogen peroxide , at moderate concentrations (5 μM), significantly enhances cystathionine γ-lyase promoter activity and mRNA/protein expression, suggesting a potential feedback loop where cystathionine γ-lyase -derived hydrogen sulfide scavenges reactive oxygen species. Hypoxia regulates cystathionine γ-lyase through transcriptional and post-transcriptional mechanisms, with increased cystathionine γ-lyase expression potentially protecting cells by elevating hydrogen sulfide levels and buffering oxygen consumption. Furthermore, lipopolysaccharide-induced cystathionine γ-lyase expression critically depends on the Nuclear Factor κB transcription factor binding site (GGACATTCC) within the cystathionine γ-lyase promoter, establishing a direct link between inflammatory signaling and hydrogen sulfide biosynthesis. Based on these findings, we propose a mechanistic hypothesis wherein hypoxia-induced cardiomyocyte apoptosis releases hydrogen peroxide, which activates Nuclear Factor κB signaling in vascular endothelial cells to upregulate cystathionine γ-lyase expression, leading to enhanced hydrogen sulfide production and subsequent vasodilation. Understanding these regulatory networks provides theoretical foundations for developing therapeutic strategies targeting the cystathionine γ-lyase/hydrogen sulfide pathway in cardiovascular diseases, including myocardial infarction, hypertension, and atherosclerosis.
Keywords: Cystathionine γ-lyase; Hydrogen sulfide; Hypoxia; Nuclear Factor κB; Cardiovascular regulation