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

摘要

Hydrogen sulfide (H_2S) 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 H_2S reduced aortic atherosclerotic plaque formation with reduction in super-oxide (O_2~-) generation and the adhesion molecules in streptozotocin (STZ)-induced LDLr~(-/-) mice but not in LDLr~(-/-)Nrf2~(-/-) mice. In vitro, H_2S inhibited foam cell formation, decreased O_2~- generation, and increased nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translo-cation 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. H_2S also decreased O_2~- 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. H_2S increased S-sulfhydration of Keap1, induced Nrf2 dissociation from Keap1, enhanced Nrf2 nuclear translocation, and inhibited O_2~- generation, which were abrogated after Keap1 mutated at Cys151, but not Cys273, in endothelial cells. Collectively, H_2S attenuates diabetes-accelerated atherosclerosis, which may be related to inhibition of oxidative stress via Keap1 sulfhy-drylation at Cys151 to activate Nrf2 signaling. This may provide a novel therapeutic target to prevent atherosclerosis in the context of diabetes.