title: Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation.
abstract: Hydrogen sulfide (H2S) has been shown to have powerful antioxidative and anti-inflammatory properties that can regulate multiple cardiovascular functions. However, its precise role in diabetes-accelerated atherosclerosis remains unclear. We report here that H2S reduced aortic atherosclerotic plaque formation with reduction in superoxide (O2 (-)) generation and the adhesion molecules in streptozotocin (STZ)-induced LDLr(-/-) mice but not in LDLr(-/-)Nrf2(-/-) mice. In vitro, H2S inhibited foam cell formation, decreased O2 (-) generation, and increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and consequently heme oxygenase 1 (HO-1) expression upregulation in high glucose (HG) plus oxidized LDL (ox-LDL)-treated primary peritoneal macrophages from wild-type but not Nrf2(-/-) mice. H2S also decreased O2 (-) and adhesion molecule levels and increased Nrf2 nuclear translocation and HO-1 expression, which were suppressed by Nrf2 knockdown in HG/ox-LDL-treated endothelial cells. H2S increased S-sulfhydration of Keap1, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and inhibited O2 (-) generation, which were abrogated after Keap1 mutated at Cys151, but not Cys273, in endothelial cells. Collectively, H2S attenuates diabetes-accelerated atherosclerosis, which may be related to inhibition of oxidative stress via Keap1 sulfhydrylation at Cys151 to activate Nrf2 signaling. This may provide a novel therapeutic target to prevent atherosclerosis in the context of diabetes.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Xie
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Wen
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
authors.forename: Wan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Meng
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore, Singapore.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Moore
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, U.K.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Metabolic Disease Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Third Affiliated Hospital of Harbin Medical University, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K.
authors.forename: Albert
authors.initials: A
authors.lastname: Ferro
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China yongji@njmu.edu.cn huangzhengrong@xmu.edu.cn.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China yongji@njmu.edu.cn huangzhengrong@xmu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000097:blood / Q000503:physiopathology*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000097:blood* / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: C529376:GYY 4137; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D009025:Morpholines; D051267:NF-E2-Related Factor 2; D009946:Organothiophosphorus Compounds; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D005947:Glucose; D006862:Hydrogen Sulfide