The hydrogen sulfide donor, GYY4137, exhibits anti-atherosclerotic activity in high fat fed apolipoprotein E(-/-) mice

Br J Pharmacol. 2013 Aug;169(8):1795-809. doi: 10.1111/bph.12246.


Background and purpose: 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.

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 Ser(473) 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.

Keywords: arteriosclerosis; endothelial dysfunction; hydrogen sulfide; inflammation; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Apolipoproteins E
  • Atherosclerosis / chemically induced
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / metabolism
  • Cells, Cultured
  • Cholesterol / metabolism
  • Diet, High-Fat
  • Down-Regulation
  • Endothelium, Vascular / metabolism*
  • Female
  • Foam Cells / drug effects
  • Humans
  • I-kappa B Proteins
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-6 / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Morpholines / pharmacology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II
  • Organothiophosphorus Compounds / pharmacology*
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Scavenger Receptors, Class E / drug effects
  • Scavenger Receptors, Class E / metabolism
  • Superoxides / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Apolipoproteins E
  • GYY 4137
  • I-kappa B Proteins
  • Interleukin-6
  • Morpholines
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • OLR1 protein, human
  • Organothiophosphorus Compounds
  • Scavenger Receptors, Class E
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Superoxides
  • Intercellular Adhesion Molecule-1
  • NF-KappaB Inhibitor alpha
  • Cholesterol
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Phosphatidylinositol 3-Kinases