Hydrogen sulfide ameliorates endothelial dysfunction in aging arteries by regulating ferroptosis

Aging causes vascular endothelial dysfunction. We aimed to investigate the causes of vascular endothelial dysfunction during aging using plasma and renal arteries from patients who underwent nephrectomy and animal models. The results showed that the endogenous H₂S-producing enzyme cystathione-γ-lyase (CSE) protein expression was downregulated in renal artery tissue, plasma H₂S levels were reduced. Moreover, elevated lipid peroxidation and iron accumulation levels led to ferroptosis and endothelial diastolic function in the renal arteries was impaired in the elderly group. H₂S enhanced the endogenous CSE expression in the elderly group, promoted endogenous H₂S production, decreased lipid peroxide expression, and inhibited ferroptosis, which in turn improved vascular endothelial function in the elderly group. In animal models, we also observed the same results. In addition, we applied NaHS, Ferrostatin-1 (ferroptosis inhibitor) and erastin (ferroptosis inducer) to incubate renal arteries of SD rats. The results showed that NaHS enhanced ferroptosis related proteins expression, inhibited ferroptosis and improved vascular endothelial function. We demonstrated that endothelial dysfunction associated with aging is closely related to reduced endogenous H₂S levels and ferroptosis in vascular endothelial cells. Notably, H₂S reduced lipid peroxidation levels in vascular endothelial cells, inhibited ferroptosis in vascular endothelial cells, and improved endothelial dysfunction.