title: Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2.
abstract: OBJECTIVE
  H2S, a third member of gasotransmitter family along with nitric oxide and carbon monoxide, exerts a wide range of cellular and molecular actions in our body. Cystathionine gamma-lyase (CSE) is a major H2S-generating enzyme in our body. Aging at the cellular level, known as cellular senescence, can result from increases in oxidative stress. The aim of this study was to investigate how H2S attenuates oxidative stress and delays cellular senescence.
  
  
  RESULTS
  Here we showed that mouse embryonic fibroblasts isolated from CSE knockout mice (CSE KO-MEFs) display increased oxidative stress and accelerated cellular senescence in comparison with MEFs from wild-type mice (WT-MEFs). The protein expression of p53 and p21 was significantly increased in KO-MEFs, and knockdown of p53 or p21 reversed CSE deficiency-induced senescence. Incubation of the cells with NaHS (a H2S donor) significantly increased the glutathione (GSH) level and rescued KO-MEFs from senescence. Nrf2 is a master regulator of the antioxidant response, and Keap1 acts as a negative regulator of Nrf2. NaHS S-sulfhydrated Keap1 at cysteine-151, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and stimulated mRNA expression of Nrf2-targeted downstream genes, such as glutamate-cysteine ligase and GSH reductase.
  
  
  METHODS
  These results provide a mechanistic insight into how H2S signaling mediates cellular senescence induced by oxidative stress.
  
  
  CONCLUSIONS
  H2S protects against cellular aging via S-sulfhydration of Keap1 and Nrf2 activation in association with oxidative stress.
authors.affiliation: Cardiovascular and Metabolic Research Unit, Lakehead University, Ontario P7B 5E1, Canada.
authors.forename: Guangdong
authors.initials: G
authors.lastname: Yang
authors.forename: Kexin
authors.initials: K
authors.lastname: Zhao
authors.forename: Youngjun
authors.initials: Y
authors.lastname: Ju
authors.forename: Sarathi
authors.initials: S
authors.lastname: Mani
authors.forename: Qiuhui
authors.initials: Q
authors.lastname: Cao
authors.forename: Stephanie
authors.initials: S
authors.lastname: Puukila
authors.forename: Neelam
authors.initials: N
authors.lastname: Khaper
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D003542:Cystathionine gamma-Lyase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D003542:Cystathionine gamma-Lyase; D005978:Glutathione; D003545:Cysteine; D006862:Hydrogen Sulfide