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Diabetes. 2016 Oct;65(10):3171-84. doi: 10.2337/db16-0020. Epub 2016 Jun 22.

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation.

Author information

1
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.
2
Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
3
Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
4
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
5
Department of Pharmacology, National University of Singapore, Singapore, Singapore.
6
Faculty of Life Sciences, The University of Manchester, Manchester, U.K.
7
Center for Metabolic Disease Research, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA.
8
The Third Affiliated Hospital of Harbin Medical University, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China.
9
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
10
Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K.
11
Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, China yongji@njmu.edu.cn huangzhengrong@xmu.edu.cn.
12
Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China yongji@njmu.edu.cn huangzhengrong@xmu.edu.cn.

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.

PMID:
27335232
DOI:
10.2337/db16-0020
[Indexed for MEDLINE]
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