title: The hydrogen sulfide donor, GYY4137, exhibits anti-atherosclerotic activity in high fat fed apolipoprotein E(-/-) mice.
abstract: OBJECTIVE
  Atherosclerosis is associated with reduced vascular hydrogen sulfide (H2 S) biosynthesis. GYY4137 is a novel slow-releasing H2 S compound that may effectively mimic the time course of H2 S release in vivo. However, it is not known whether GYY4137 affects atherosclerosis.
  
  
  METHODS
  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.
  
  
  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 Ser(473) phosphorylation and down-regulated the expression of LOX-1.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research Centre, Nanjing Medical University, Nanjing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.forename: Guoliang
authors.initials: G
authors.lastname: Meng
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Li
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shirhan
authors.forename: Meng Teng
authors.initials: MT
authors.lastname: Peh
authors.forename: Liping
authors.initials: L
authors.lastname: Xie
authors.forename: Suming
authors.initials: S
authors.lastname: Zhou
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Weilu
authors.initials: W
authors.lastname: Dai
authors.forename: Choon-Hong
authors.initials: CH
authors.lastname: Tan
authors.forename: Shiyang
authors.initials: S
authors.lastname: Pan
authors.forename: Philip K
authors.initials: PK
authors.lastname: Moore
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005487:Foam Cells / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051127:Scavenger Receptors, Class E / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C529376:GYY 4137; D020672:I-kappa B Proteins; D015850:Interleukin-6; D009025:Morpholines; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C495137:OLR1 protein, human; D009946:Organothiophosphorus Compounds; D051127:Scavenger Receptors, Class E; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D002784:Cholesterol; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases
keywords: arteriosclerosis; endothelial dysfunction; hydrogen sulfide; inflammation; oxidative stress