Role of Hydrogen Sulfide Regulation of Programmed Cell Death: Implications for Cardiovascular Diseases

Significance: Hydrogen sulfide (H₂S) is an important signaling molecule involved in cardiovascular diseases (CVDs). Although it is important, the precise mechanisms underlying the diverse functions of H₂S in CVDs are not known and need to be elucidated. Recent Advances: Studies have shown the importance of different programmed cell death (PCD) modalities, such as NETosis, apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, in the pathogenesis of CVDs. An overview of the role of H₂S in regulating PCD in diabetic cardiomyopathy (DCM), cardiac hypertrophy and fibrosis, hypertension, heart failure, atherosclerosis and myocardial ischemia/reperfusion injury, might provide a better understanding of the cardiovascular effects of H₂S. Critical Issues: The mechanisms by which H₂S modulates each type of PCD in CVD patients need to be elucidated. The differences in the effects of H₂S on PCD modalities in different cardiovascular cell types, such as cardiomyocytes, endothelial cells, smooth muscle cells, and immune cells, require further evidence. Future Directions: Future studies should focus on the mechanism by which H₂S affects distinct PCD pathways. Whether H₂S acts as a switch between different PCD pathways under stress or disease conditions needs to be determined. H₂S might regulate the temporal and spatial overlapping PCD pathways in CVDs. Single-cell RNA sequences, spatial transcriptomics, and live-cell imaging are needed to map PCD events regulated by H₂S. Innovation: In this review, we summarized the regulatory effects of H₂S on signaling pathways related to PCD in patients with CVDs. Understanding these mechanisms is crucial for elucidating the pathophysiological roles of H₂S in CVDs. Antioxid. Redox Signal. 43, 637-690.