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.

Background and Purpose Atherosclerosis is associated with reduced vascular hydrogen sulfide (H2S) biosynthesis. GYY4137 is a novel slow‐releasing H2S compound that may effectively mimic the time course of H2S release in vivo. However, it is not known whether GYY4137 affects atherosclerosis. Experimental Approach RAW 264.7 cells and human blood monocyte‐derived macrophages were incubated with oxidized low density lipoprotein (ox‐LDL) with/without GYY4137. ApoE−/− mice were fed a high‐fat diet for 4 weeks and administered GYY4137 for 30 days. Lipid and atherosclerotic lesions were measured by oil red O staining. Endothelium‐dependent relaxation was assessed in response to acetylcholine. Superoxide production was detected by dihydroethidium staining. Expression of mRNA and protein were evaluated by quantitative real‐time PCR and Western blot. Key Results GYY4137 inhibited ox‐LDL‐induced foam cell formation and cholesterol esterification in cultured cells. GYY4137 decreased the expression of lectin‐like ox‐LDL receptor‐1, iNOS, phosphorylated IκBα, NF‐κB, ICAM‐1, VCAM‐1 and chemokines, including CXCL2, CXCR4, CXCL10 and CCL17, but increased the scavenger protein CD36, in ox‐LDL‐treated RAW 264.7 cells. In vivo, GYY4137 decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium‐dependent relaxation in apoE−/− mice. GYY4137 decreased ICAM‐1, TNF‐α and IL‐6 mRNA expression as well as superoxide (O2−) generation in aorta. In addition, GYY4137 increased aortic eNOS phosphorylation and expression of PI3K, enhanced Akt Ser473 phosphorylation and down‐regulated the expression of LOX‐1. Conclusion and Implications GYY4137 inhibits lipid accumulation induced by ox‐LDL in RAW 264.7 cells. In vivo, GYY4137 decreased vascular inflammation and oxidative stress, improved endothelial function and reduced atherosclerotic plaque formation in apoE−/− mice.

As the most abundant natural flavonoid in rattan tea, dihydromyricetin (DMY) has shown a wide range of pharmacological effects. In addition to the general characteristics of flavonoids, DMY has the effects of cardioprotection, anti-diabetes, hepatoprotection, neuroprotection, anti-tumor, and dermatoprotection. DMY was also applied for the treatment of bacterial infection, osteoporosis, asthma, kidney injury, nephrotoxicity and so on. These effects to some extent enrich the understanding about the role of DMY in disease prevention and therapy. However, to date, we still have no outlined knowledge about the detailed mechanism of DMY, which might be related to anti-oxidation and anti-inflammation. And the detailed mechanisms may be associated with several different molecules involved in cellular apoptosis, oxidative stress, and inflammation, such as AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), protein kinase B (Akt), nuclear factor-κB (NF-κB), nuclear factor E2-related factor 2 (Nrf2), ATP-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-γ (PPARγ) and so on. Here, we summarized the current pharmacological developments of DMY as well as possible mechanisms, aiming to push the understanding about the protective role of DMY as well as its preclinical assessment of novel application.

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.