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.

Gold nanoparticles reduce high glucose-induced oxidative-nitrosative stress regulated inflammation and apoptosis via tuberin-mTOR/NF-κB pathways in macrophages

“…2 HG-induced reactive oxygen/nitrogen species (ROS/RNS) overproduction may be a key event in activation of signaling pathways involved in the pathogenesis of atherosclerosis. 2,3 Interestingly, the mechanism of autoxidation describes the capability of glucose to enolize, thereby reducing molecular oxygen and yielding oxidizing intermediates, including superoxide anion (O 2 When macrophages respond to HG, ROS/RNS production was increased in cellular compartments and these reactive species triggered DNA strand breakage, leading to rapid increase in amounts of 8-hydroxydeoxyguanosine in DNA and decreases in the amount of DNA repair enzyme 8-oxoguanine glycosylase (OGG1). 2 Recent studies have revealed that HG-induced cellular changes lead to alterations of signal transduction cascades in macrophages, affecting gene expression and protein functions both in mitochondria and nuclei.…”

“…2 Many studies have demonstrated that antioxidants and Akt/ERK1/2 inhibitors abolished HG-induced Akt/ERK1/2 expression in macrophages, thus implicating ROS/RNS and kinases as signaling molecules in this effect. 3,11 Ferenbach et al 12 demonstrated that resident kidney cells and infiltrating monocytes secreted the proinflammatory mediators such as cytokines, chemokines and growth factors in response to hyperglycemia. Recent publications have revealed that release of cytokines, including tumor necrosis factor-α (TNF-α)-, interleukin-6, and interleukin-1β due to hyperglycemia further aggravated the inflammatory infiltration and immune responses in the pathology of diabetic complications in macrophages.…”

“…3,35 More importantly, cells contain a large number of antioxidants to prevent or repair the damage caused by ROS/RNS, as well as regulate redox-sensitive signaling cascades in diverse cell types during hyperglycemia. 4 37 Similarly, the GPx reduces organic hydroperoxides, while GSH helps in the redox regulation of cellular compartments and offers a defense mechanism against oxidant stress in a thiol-sensitive fashion.…”

Hydrogen Sulfide Therapy in Diabetes-Accelerated Atherosclerosis: A Whiff of Success

“…Significantly, deletion or silencing of Nrf2 abolishes the antiatherogenic action of GYY4137 in diabetic mice and cells, illustrating the essential role of Nrf2. In addition, GYY4137 stimulates the expression of heme oxygenase 1 (HO-1) in an Nrf2-dependent manner, and depletion or inhibition of HO-1 abolishes the cellular actions of GYY4137, implicating HO-1 in the antiatherogenic effects of H 2 S. Notably, Xie et al (11) detect significantly lower levels of plasma H 2 S in diabetic mice that is corrected by the administration of GYY4137. A reduction in circulating H 2 S has also been noted in other diabetic animal models and patients with diabetes (7,(13)(14)(15), supporting the presence of an H 2 S deficiency state in diabetes.…”

“…The study by Xie et al (11) represents an important advance in the field and identifies H 2 S as a novel therapeutic target in diabetes-accelerated atherosclerosis. The finding that Nrf2 functions as the initial transducer of the antiatherogenic action of H 2 S is somewhat surprising given the controversial role of Nrf2 in atherosclerosis (16), but it is in line with a recent report showing that Nrf2 activation represses atherosclerosis in a mouse model of diabetes (17).…”