Hydrogen sulfide prevents homocysteine-induced endoplasmic reticulum stress in PC12 cells by upregulating SIRT-1

Abstract

It was previously confirmed that hydrogen sulfide (H2S) has a neuroprotective effect, preventing homocysteine‑induced neurotoxicity. However, the exact molecular mechanisms underlying this protective effect remain to be fully elucidated. Endoplasmic reticulum (ER) stress contributes to homocysteine‑induced neurotoxicity. Silent mating type information regulator 2 homolog 1 (SIRT‑1) can attenuate ER stress, exerting its neuroprotective effect. Therefore, the present study aimed to investigate whether H2S protects PC12 cells against homocysteine‑induced ER stress and whether SIRT‑1 mediates this protective effect of H2S. Western blotting was used to detect the expression of SIRT‑1, glucose‑regulated protein 78 (GRP78), and cleaved caspase‑12 in PC12 cells. It was observed that sodium hydrosulfide (NaHS), an exogenous H2S donor, significantly attenuated the homocysteine‑induced ER stress responses, including increases in the protein expression levels of GRP78 and cleaved caspase‑12. Simultaneously, NaHS upregulated the expression of SIRT‑1 and reversed the homocysteine‑induced downregulation of SIRT‑1 in PC12 cells. Sirtinol, a specific inhibitor of SIRT‑1, eliminated the protective effects of H2S in homocysteine‑induced ER stress. These data indicated that H2S prevented homocysteine‑induced ER stress via enhancing the expression of SIRT‑1. These findings offer novel insight into the protective mechanisms of H2S against homocysteine‑induced neurotoxicity.

Hydrogen Sulfide Inhibits Homocysteine-Induced Neuronal Senescence by Up-Regulation of SIRT1

“…Numerous studies have demonstrated that SIRT1 ameliorate neurodegenerative disease, such as AD [55], PD [56], subarachnoid hemorrhage [57], which reveal that SIRT1 delays senescence in the brain. Our previous study demonstrated that SIRT1 mediates the protective effect of H 2 S on Hcy-induced neurotoxicity [20]. Therefore, we speculated whether SIRT1 mediates the protection of H 2 S against Hcy-induced senescence in HT22 cells.…”

“…Our previous studies have demonstrated that H 2 S has a protective effect against Hcy-evoked neurotoxicity [20,[24][25][26]. Considering the cellular senescence is prominent in the neurotoxicity of Hcy [3,[27][28][29], the present work was designed to explore whether the protection of H2S against the neurotoxicity of Hcy is associated with regulating neuronal senescence.…”

“…Therefore, the regulation of neuronal senescence offers insights into the protection of H2S against the neurotoxicity of Hcy. In our previous work, we used PC12 cells as a cell model to explore the protection of H2S against Hcy-induced endoplasmic reticulum (ER) stress [20]. This previous work focused on the protective role of H 2 S in Parkinson's disease.…”

“…Recently, it has shown that H2S extends lifespan by activation of SIRT1 [12]. Furthermore, Our previous data demonstrated that H 2 S up-regulates the expression of SIRT1 in PC12 cells [20]. Thus, we further investigated whether SIRT1 mediates the inhibitory role of H 2 S in Hcy-induced neuronal senescence.…”

“…Previous studies revealedthat H 2 S protects endothelial cells against nicotinamide- [17] and H 2 O 2 - [18] induced cellular senescence. Our previous study indicated that H 2 S prevents Hcy-induced neurotoxicity [19,20]. In this study, we explored whether ameliorating Hcy-induced neuronal senescence contributes to the protection of H 2 S against Hcy-induced neurotoxicity.…”