Regulation of Cystathionine ?-Lyase Expression in the Cardiovascular System: Insights into Exogenous H2S, H2O2, Hypoxia, and NF-?B Signaling

Abstract

Cystathionine ?-lyase (CSE) is a key enzyme in the transsulfuration pathway responsible for endogenous hydrogen sulfide (H2S) production in the cardiovascular system. As the third gaseous signaling molecule, H2S plays crucial roles in maintaining vascular homeostasis, regulating vasodilation, and protecting against ischemia-reperfusion injury. This review comprehensively analyzes the regulatory mechanisms governing CSE expression under various physiological and pathological conditions. Exogenous H2S exhibits concentration-dependent bidirectional regulation of CSE expression, with lower concentrations (10-80 uM) suppressing CSE through feedback inhibition, while higher concentrations (120-160 uM) upregulating its expression as a protective response. Hydrogen peroxide (H2O2), at moderate concentrations (5 uM), significantly enhances CSE promoter activity and mRNA/protein expression, suggesting a potential feedback loop where CSE-derived H2S scavenges reactive oxygen species. Hypoxia regulates CSE through transcriptional and post-transcriptional mechanisms, with increased CSE expression potentially protecting cells by elevating H2S levels and buffering oxygen consumption. Furthermore, lipopolysaccharide (LPS)-induced CSE expression critically depends on the NF-?B transcription factor binding site (GGACATTCC) within the CSE promoter, establishing a direct link between inflammatory signaling and H2S biosynthesis. Based on these findings, we propose a mechanistic hypothesis wherein hypoxia-induced cardiomyocyte apoptosis releases H2O2, which activates NF-?B signaling in vascular endothelial cells to upregulate CSE expression, leading to enhanced H2S production and subsequent vasodilation. Understanding these regulatory networks provides theoretical foundations for developing therapeutic strategies targeting the CSE/H2S pathway in cardiovascular diseases, including myocardial infarction, hypertension, and atherosclerosis.