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Hydrogen sulfide induces Keap1 S-sulfhydration and suppresses diabetes-accelerated atherosclerosis via Nrf2 activation

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Liping Xie, Yue Gu, Mingliang Wen, Shuang Zhao, Wan Wang, Yan Ma, Guoliang Meng, Yi Han, Yuhui Wang, George Liu, Philip K. Moore, Xin Wang, Hong Wang, Zhiren Zhang, Ying Yu, Albert Ferro, Zhengrong Huang, Yong Ji

Original languageEnglish
Pages (from-to)3171-3184
Number of pages14
JournalDiabetes
Volume65
Issue number10
Early online date22 Sep 2016
DOIs
Accepted/In press15 Jun 2016
E-pub ahead of print22 Sep 2016
Published1 Oct 2016

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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.

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