Hydrogen sulfide alleviates vascular smooth muscle cell senescence by inhibiting endoplasmic reticulum stress

The senescence of vascular smooth muscle cells (VSMCs) leads to the degeneration of vascular structure and function, as well as age-related cardiovascular diseases. Hydrogen sulfide (H₂S) has been proven to suppress the progression of various cardiovascular diseases by decreasing endoplasmic reticulum (ER) stress, but it remains unclear whether it can inhibit ER stress to alleviate the senescence of VSMCs. In the present study, the results of cell experiments showed that 10 g/L D-galactose (D-gal) increased the VSMCs senescence, oxidative stress, the expression of ER stress related proteins (GRP78, CHOP) and up-regulated pathways of IRE1-XBP1, PERK-eIF-2 α-ATF4 and ATF6 as well as decreased the expression of the cystathionine gamma-lyase (CSE) and H₂S production. H₂S supplement significantly reversed the effect of D-gal on the above indicators. Meanwhile, we also observed similar results in vascular tissues of naturally aged mice. In addition, naturally aged mice exhibited reduction of vascular elastic fibers and accumulation of collagen fibers as well as thickening of the vascular wall, while supplementation with H₂S was able to alleviate these phenomena. At the same time, we also found that H₂S could restore the S-sulfhydration level of GRP78. The knockdown and the Cys42 mutation in GRP78 completely abrogated H₂S-mediated suppression of VSMCs senescence by decreasing ER stress. Our results suggest that H₂S can delay the senescence of VSMCs by decreasing ER stress by down-regulating IRE1-XBP1, PERK-eIF-2α-ATF4 and ATF6 pathways via increasing the S-sulfhydration level of GRP78 by the Cys42 site.