title: SIRT3 Mediates the Antioxidant Effect of Hydrogen Sulfide in Endothelial Cells.
abstract: OBJECTIVE
  Oxidative stress is a key contributor to endothelial dysfunction and associated cardiovascular pathogenesis. Hydrogen sulfide (H2S) is an antioxidant gasotransmitter that protects endothelial cells against oxidative stress. Sirtuin3 (SIRT3), which belongs to the silent information regulator 2 (SIR2) family, is an important deacetylase under oxidative stress. H2S is able to regulate the activity of several sirtuins. The present study aims to investigate the role of SIRT3 in the antioxidant effect of H2S in endothelial cells.
  
  
  RESULTS
  Cultured EA.hy926 endothelial cells were exposed to hydrogen peroxide (H2O2) as a model of oxidative stress-induced cell injury. GYY4137, a slow-releasing H2S donor, improved cell viability, reduced oxidative stress and apoptosis, and improved mitochondrial function following H2O2 treatment. H2S reversed the stimulation of MAPK phosphorylation, downregulation of SIRT3 mRNA and reduction of the superoxide dismutase 2 and isocitrate dehydrogenase 2 expression which were induced by H2O2. H2S also increased activator protein 1 (AP-1) binding activity with SIRT3 promoter and this effect was absent in the presence of the specific AP-1 inhibitor, SR11302 or curcumin. Paraquat administration to mice induced a defected endothelium-dependent aortic vasodilatation and increased oxidative stress in both mouse aorta and small mesenteric artery, which were alleviated by GYY4137 treatment. This vasoprotective effect of H2S was absent in SIRT3 knockout mice.
  
  
  METHODS
  The present results highlight a novel role for SIRT3 in the protective effect of H2S against oxidant damage in the endothelium both in vitro and in vivo.
  
  
  CONCLUSIONS
  H2S enhances AP-1 binding activity with the SIRT3 promoter, thereby upregulating SIRT3 expression and ultimately reducing oxidant-provoked vascular endothelial dysfunction. Antioxid. Redox Signal. 24, 329-343.
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Liping
authors.initials: L
authors.lastname: Xie
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Haihua
authors.initials: H
authors.lastname: Feng
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .|2 Department of Pharmacology, School of Pharmacy, Nantong University , Nantong, China .
authors.forename: Guoliang
authors.initials: G
authors.lastname: Meng
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Shangmin
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: 3 Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University , Nanjing, China .
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Yue
authors.initials: Y
authors.lastname: Gu
authors.affiliation: 4 Department of Cardiothoracic Surgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, China .
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Shao
authors.affiliation: 5 Department of Chemistry, Washington State University , Pullman, Washington.
authors.forename: Chung-Min
authors.initials: CM
authors.lastname: Park
authors.affiliation: 5 Department of Chemistry, Washington State University , Pullman, Washington.
authors.forename: Ming
authors.initials: M
authors.lastname: Xian
authors.affiliation: 6 Institute of Vascular Biology, Chinese University of Hong Kong , Hong Kong, China .
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 7 Cardiovascular Division, Department of Clinical Pharmacology, School of Medicine, King's College London , London, United Kingdom .
authors.forename: Albert
authors.initials: A
authors.lastname: Ferro
authors.affiliation: 8 Department of Biology, Cardivascular and Molecular Research Unit, Lakehead University , Thunder Bay, Ontario, Canada .
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: 9 Department of Pharmacology, National University of Singapore , Singapore .
authors.forename: Philip K
authors.initials: PK
authors.lastname: Moore
authors.affiliation: 10 Department of Pharmacology, Center for Metabolic Disease Research, Temple University School of Medicine , Philadelphia, Pennsylvania.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: 1 Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University , Nanjing, China .
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D056566:Sirtuin 3; D006862:Hydrogen Sulfide