The protective effects of endogenous hydrogen sulfide modulator, S-propargyl-cysteine, on high glucose-induced apoptosis in cardiomyocytes: A novel mechanism mediated by the activation of Nrf2

Abstract

S-propargyl-cysteine (SPRC) is a novel synthetic molecule exerting antioxidant effects via elevating generation of endogenous H2S. Our study aimed to elucidate possible antioxidant mechanisms of SPRC in hyperglycemia-induced oxidative stress. H9C2 cells were treated with SPRC or NaHS at the indicated concentration before being treated with high glucose for 48h. Follow-up experiments were based on detailed description given in Section 2. SD rats were injected with Streptozocin (STZ) to induce diabetes as previously reported. Diabetic rats were administrated with SPRC, NaHS or solution respectively for one week before the rats were killed for follow-up experiments. Our work found that SPRC remarkably attenuated high glucose induced generation of reactive oxygen species and apoptosis in H9C2 cells. SPRC increased stability and nuclear translocation of Nuclear factor erythroid 2-related factor 2 (Nrf2), up-regulated expression of antioxidant enzyme superoxide dismutase (SOD) and interfered with the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and Nrf2. SPRC activated Nrf2 via Cystathionase-γ-lyase (CSE) and Akt pathway. CSE inhibitor PAG and Akt inhibitor LY294002 could reverse the protective effects of SPRC. Knockdown of Nrf2 by shRNA also blocked SPRC up-regulated expression of CSE. Similar results of protein expression and hypoglycemic activity of SPRC were observed in STZ induced diabetic rats.

Keywords: Cystathionase-γ-lyase; High glucose; NF-E2-related factor 2; Reactive oxygen species; S-propargyl-cysteine.