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

Abstract

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.

• Authors: Zhen Liu, Yi Han, Ling Li, Hui Lu, Guoliang Meng, Xiaozhen Li, Mohammed Shirhan, Meng Teng Peh, Liping Xie, Suming Zhou, Xiaowei Wang, Qi Chen, Weilu Dai, Choon-Hong Tan, Shiyang Pan, Philip K Moore, Yong Ji
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 169 Issue 8 Pg. 1795-809 (Aug 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23713790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• 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

Topics

• Animals
• Aorta (metabolism)
• Apolipoproteins E
• Atherosclerosis (chemically induced, drug therapy, 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, 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, metabolism)
• Superoxides (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Cell Adhesion Molecule-1 (metabolism)