Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation.
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 +17 more
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H2S attenuates diabetes-accelerated atherosclerosis, which may be related to inhibition of oxidative stress via Keap1 sulfhydrylation at Cys151 to activate Nrf2 signaling.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.read more
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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
Antonio Cuadrado,Ana I. Rojo,Geoffrey Wells,John D. Hayes,Sharon P. Cousin,William L. Rumsey,Attucks Otis Clinton,Stephen Franklin,Anna-Liisa Levonen,Thomas W. Kensler,Albena T. Dinkova-Kostova,Albena T. Dinkova-Kostova +11 more
TL;DR: An overview of the physiological and pathological roles of NRF2 is provided, emerging pharmacological modulators of theNRF2–KEAP1 axis are presented and associated drug development challenges are highlighted.
Journal ArticleDOI
New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis.
Ting Yuan,Ting Yang,Huan Chen,Danli Fu,Yangyang Hu,Jing Wang,Qing Yuan,Hong Yu,Wenfeng Xu,Xiang Xie +9 more
TL;DR: The consequences of the sustained increase of ROS production and inflammation that influence the acceleration of atherosclerosis by diabetes are highlighted and the potential contributions of changes in the gut microbiota and microRNA expression are discussed.
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International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors.
TL;DR: The present article overviews the currently known H 2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
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Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide
TL;DR: Hydrogen sulfide (H2S), an entry as a gasotransmitter, exerts diverse biological effects through acting on various targeted signaling pathways and is postulated to be a new indicator for endothelial cell inflammation and its associated endothelial dysfunction.
Journal ArticleDOI
Macrophage functions in lean and obese adipose tissue.
TL;DR: The various functions of macrophages in lean and obese adipose tissue and how obesity alters macrophage phenotypes are reviewed to help understand the molecular mechanisms underlying these processes and their therapeutic implications for obesity, metabolic syndrome, and diabetes.
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