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Xie L , Gu Y , Wen M , Zhao S , Wang W , Ma Y , Meng G , Han Y , Wang Y , Liu G , Moore PK , Wang X , Wang H , Zhang Z , Yu Y , Ferro A , Huang Z , Ji Y
Hydrogen sulfide induces keap1 S-sulfhydration and suppresses diabetes-accelerated atherosclerosis via Nrf2 activation
Diabetes. 2016 Oct;65(10) :3171-84
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Hydrogen sulfide (H2S) has been shown to have powerful anti-oxidative and anti-inflammatory properties which 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, as well as increased Nrf2 nuclear translocation and consequently heme oxygenase-1 (HO-1) expression up-regulation in high-glucose (HG) plus oxidized low density lipoprotein (ox-LDL)-treated primary peritoneal macrophages from wild-type but not Nrf2-/- mice. H2S also decreased O2 - and adhesion molecules levels, 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 Keapl, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation and inhibited O2 - generation which were abrogated after Keapl 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.
Xie, Liping Gu, Yue Wen, Mingliang Zhao, Shuang Wang, Wan Ma, Yan Meng, Guoliang Han, Yi Wang, Yuhui Liu, George Moore, Philip K Wang, Xin Wang, Hong Zhang, Zhiren Yu, Ying Ferro, Albert Huang, Zhengrong Ji, Yong Diabetes. 2016 Jun 22. pii: db160020.