title: 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Hebei
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China; Department of Pharmacology, Loo Yong Lin School of Medicine, National University of Singapore, Singapore, Singapore. Electronic address: zhuyz@fudan.edu.cn.
authors.forename: Yizhun
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019610:Cytoprotection; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; C556437:S-propargylcysteine; D051057:Proto-Oncogene Proteins c-akt; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D006862:Hydrogen Sulfide
keywords: Cystathionase-γ-lyase; High glucose; NF-E2-related factor 2; Reactive oxygen species; S-propargyl-cysteine