GYY4137 exhibits anti-atherosclerosis effect in apolipoprotein E (-/-) mice via PI3K/Akt and TLR4 signalling.

Abstract

Hydrogen sulphide (H2 S) had been suggested to be involved in the pathogenesis of atherosclerosis, but the underlying molecular mechanisms are poorly understood. In this study, we aimed to investigate the anti-atherosclerosis effect of morpholin-4-ium-methoxyphenyl-morpholino-phosphinodithioate (GYY4137) in RAW264.7 cell-derived foam cells formation and in the atherosclerotic plaque of ApoE-/- mice fed with a high-fat diet, and study the underlying mechanisms of phosphatidylinositol 3-kinase (PI3K), serine/ threonine kinase (Akt) and Toll-like receptor 4 (TLR4) signalling pathway. In the ApoE-/- mice fed with a high-fat diet, daily GYY4137 administration for 8weeks effectively decreased carotid atherosclerotic plaque area and the volume of foam cells, regulated the lipid metabolism, down-regulated the pro-inflammatory cytokine levels and up-regulated the anti-inflammatory cytokines levels. Consistent with these findings, in the RAW264.7 cell-derived foam cells, GYY4137 ameliorated foam cell formation in vitro, and decreased the expression of pro-inflammatory cytokines. Furthermore, our studies showed that GYY4137 could activate the PI3K/Akt signalling pathway and consequently reduce the expression of TLR4 to be critical for foam cell formation, preventing atherosclerotic plaque formation and destabilization. LY294002, a PI3K inhibitor, could inhibit the phosphorylation of Akt and reduce the expression of TLR4, thus reduce the foam cell source and lipid volume in the unstable plaque tissue. Our results suggest that GYY4137 is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating the PI3K/Akt/TLR4 signalling pathway.