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.

Background and aimTo conduct meta-analyses of all published studies on various aspects of association between vitamin D and tuberculosis (TB).MethodsPubMed and Web of Knowledge were searched for all properly controlled studies on vitamin D and TB. Pooled odds ratio, mean difference or standardized mean difference, and its corresponding 95% confidence interval were calculated with the Cochrane Review Manager 5.3.ResultsA significantly lower vitamin D level was found in TB patients vs controls; vitamin D deficiency (VDD) was associated with an increased risk of TB, although such an association was lacking in the African population and in the human immunodeficiency virus-infected African population. A significantly lower vitamin D level was found in human immunodeficiency virus-TB-coinfected African patients receiving antiretroviral treatment who developed TB-associated immune reconstitution inflammatory syndrome vs those who did not develop TB-associated immune reconstitution inflammatory syndrome. VDD was associated with an increased risk of developing active TB in those subjects with latent TB infection and with an increased risk of tuberculin skin test conversion/TB infection conversion, and the trend toward a lower vitamin D level in active TB patients vs latent TB infection subjects did not reach statistical significance, indicating that VDD was more likely a risk factor than a consequence of TB. This concept was further strengthened by our result that anti-TB treatment did not affect vitamin D level in TB patients receiving the treatment.ConclusionOur analyses revealed an association between vitamin D and TB. VDD is more likely a risk factor for TB than its consequence. More studies are needed to determine whether vitamin D supplementation is beneficial to TB prevention and treatment.