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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\u2212) generation and the adhesion molecules in streptozotocin (STZ)-induced LDLr\u2212\/\u2212 mice but not in LDLr\u2212\/\u2212Nrf2\u2212\/\u2212 mice. In vitro, H2S inhibited foam cell formation, decreased O2\u2212 generation, and increased nuclear factor erythroid 2\u2013related factor 2 (Nrf2) nuclear translocation and consequently heme oxygenase 1 (HO-1) expression upregulation in high glucose (HG) plus oxidized LDL (ox-LDL)\u2013treated primary peritoneal macrophages from wild-type but not Nrf2\u2212\/\u2212 mice. H2S also decreased O2\u2212 and adhesion molecule levels and increased Nrf2 nuclear translocation and HO-1 expression, which were suppressed by Nrf2 knockdown in HG\/ox-LDL\u2013treated endothelial cells. H2S increased S-sulfhydration of Keap1, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and inhibited O2\u2212 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.<\/jats:p>","DOI":"10.2337\/db16-0020","type":"journal-article","created":{"date-parts":[[2016,6,24]],"date-time":"2016-06-24T01:28:32Z","timestamp":1466731712000},"page":"3171-3184","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":327,"title":["Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation"],"prefix":"10.2337","volume":"65","author":[{"given":"Liping","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China"},{"name":"Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, 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