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: 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
• Journal: Diabetes (Diabetes) Vol. 65 Issue 10 Pg. 3171-84 (10 2016) ISSN: 1939-327X [Electronic] United States
• PMID: 27335232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by the American Diabetes Association.

Chemical References

• GYY 4137
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• Lipoproteins, LDL
• Membrane Proteins
• Morpholines
• NF-E2-Related Factor 2
• Organothiophosphorus Compounds
• Receptors, LDL
• oxidized low density lipoprotein
• Heme Oxygenase-1
• Hmox1 protein, mouse
• Glucose
• Hydrogen Sulfide

Topics

• Active Transport, Cell Nucleus (drug effects)
• Animals
• Atherosclerosis (blood, drug therapy, physiopathology)
• Diabetes Mellitus (blood, physiopathology)
• Female
• Glucose (pharmacology)
• Heme Oxygenase-1 (genetics, metabolism)
• Hydrogen Sulfide (blood, metabolism)
• Kelch-Like ECH-Associated Protein 1 (metabolism)
• Lipoproteins, LDL (pharmacology)
• Macrophages, Peritoneal (drug effects, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Morpholines (pharmacology, therapeutic use)
• NF-E2-Related Factor 2 (deficiency, genetics, metabolism)
• Organothiophosphorus Compounds (pharmacology, therapeutic use)
• Protein Binding (drug effects)
• Receptors, LDL (deficiency, genetics, metabolism)