| Atherosclerosis is a pathological process of vascular remodeling, including damaged endothelial cells, the invading smoth muscle cells in vascular intima and the proliferation of vascular smooth muscle cells, which is seriously harmful to human health. There are lots of pathogenic factors contribute to the development of atherosclerosis, such as inflammation, endothelial dysfunction, oxidative stress, etc.Hydrogen sulfide (H2S) was identified as the third gaseous mediator following the nitric oxide (NO) and carbon monoxide (CO) which is also synthesized in mammals including human and played a variety of physiological activity. H2S was especially concerned for its roles in cardiovascular system such as relaxing blood vessels, inhibiting proliferation of smooth muscle cells and protecting heart against ischemia-reperfusion injury. Recently, it was reported that the aortic H2S biosynthesis and plasma H2S concentration were reduced in spontaneously atherosclerotic apoE-/-mice, coupled with the anti-atherosclerotic activity of sodium hydrosulfide (NaHS) in these animals. In addition, NaHS has been reported to inhibit the oxidized LDL (oxLDL)-evoked rise in macrophage cholesterol levels in vitro which again is indicative of a potential anti-atherosclerotic activity of this agent in vivo.However, NaHS, when dissolved in water, releases copious amounts of H2S over a short time frame (seconds) and had cytotoxic effect, as such may not effectively mimic the time course of H2S releasing in vivo. GYY4137(morpholin-4-ium-methoxyphenyl-morpholino-phosphinodithioate) is a novel H2S donor which releases H2S slowly (hours) in aqueous solution and may effectively mimic the time course of H2S releasing in vivo. Furthermore, GYY4137reduces the formation of pro-inflammatory cytokines in E Coli lipopolysaccharide (LPS)-challenged RAW264.7macrophages and LPS-treated mice. However, the effect of GYY4137on atherosclerosis is unknown.In present study, we therefore investigated the effect of GYY4137on atherosclerotic lesions in high fat fed apoE-/-mice as well as the potential mechanisms. In vivo, eight-week-old apoE-/-mice were fed high-fat diet for4weeks to accelerate the development of spontaneous atherosclerotic lesions and then were treated with GYY4137(133μmol/kg/day, i.p.,30days). There was no difference in cardiac function between C57BL/6J mice (wild-type mice, WT) and apoE-/-mice. GYY4137had no effect on the increased total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and the reduced high-density lipoprotein-cholesterol (HDL-C). GYY4137was found to reduce vascular lipid accumulation using Oil-Red O-staining in cross sections of the aortic valve area. Endothelium-dependent relaxation in aortic rings from apoE-/-mice was significantly impaired in comparison with wild-type mice. Treatment of these animals with GYY4137reversed the deficiency in acetylcholine-induced relaxation. GYY4137reversed the reduced H2S concentration in plasma and elevated H2S biosynthesis in liver. After further research the mechamisms of GYY4137anti-atherosclerotic effect, we also found GYY4137also decreased the mRNA levels of intercellular adhesion molecule-1(ICAM-1), tumor necrosis factor-a (TNF-a) and IL-6(interleukin-6) measured by real-time PCR, as well as superoxide generation in aorta, measured by the O2--sensitive fluorescent dye Dihydroethidium (DHE). Compared with NS, GYY417improved the reduced phosphorylation of eNOS serl177residue, activated the p85a (the subunit of PI3K) and phosphorylation of Akt ser473residue in aorta by western blot. GYY4137also lowered the expression of CSE and LOX-1in aorta of apoE-/-mice, and the expression of CSE and NF-κB protein in liver. In vitro, with Oil-red O staining and determination of intracellular cholesterol ester, GYY4137inhibited the formation of foam cells and the elevated intracellular cholesterol ester induced by oxidized low density lipoprotein (ox-LDL) in peripheral blood monocyte-derived macrophages (PBMCs) in healthy volunteers and patients with coronary heart disease.However, ZYJ1122, an analogue of GYY4137lacking the ability of releasing H2S, was inactive.These results indicate that GYY4137could inhibit the oxidative stress, decrease the inflammation and improve the endothelial function, therefore reduce the atherosclerotic plaque formation in apoE-/-mice. In PBMCs, GYY4137inhibits lipid deposition induced by oxLDL. All these results provide a solid reaserch basis for the wildly use and potential applications of H2S in the treatment of AS... |
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