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

Abstract

Hydrogen sulphide (H 2 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 8 weeks 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. K E Y W O R D S atherosclerosis, GYY4137, hydrogen sulphide, phosphatidylinositol 3-kinase, serine, threonine kinase, toll-like receptor 4 How to cite this article: Zheng Y, Lv P, Huang J, Ke J, Yan J. GYY4137 exhibits anti-atherosclerosis effect in apolipoprotein E (−/−) mice via PI3K/Akt and TLR4 signalling. Clin Exp

Role of PI3K in the Progression and Regression of Atherosclerosis

“…PI3K/Akt signaling was recently suggested to negatively regulate TLR4-mediated inflammation. Zheng Y et al first confirmed that morpholin-4-ium-methoxyphenyl-morpholinophosphinodithioate (GYY4137) improves foam cell formation in vitro through the PI3K/AKT and TLR4 pathways and reduces the expression of proinflammatory cytokines, thus reducing the source of foam cells and lipid volume in unstable plaque tissues (Zheng et al, 2020). The NF-κB signaling pathway has been shown in several studies to be involved in the inflammation of atherosclerotic plaques.…”

Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter

“…In a rat stomach culture model, GYY4137 increased phosphorylation of Akt and suppressed the secretion of the hunger hormone Ghrelin [ 49 ]. In apolipoprotein E KO mice, GYY4137 activated the PI3K/Akt pathway and reduced TLR4 expression, which was critical in preventing atherosclerotic plaque formation [ 50 ].…”

“… The PI3K/Akt signaling pathway. H 2 S donors (GYY4137 and NaHS) increase Akt activation, as shown in red font, arrow and lines [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Created with BioRender.com.…”

Development of hydrogen sulfide donors for anti-atherosclerosis therapeutics research: Challenges and future priorities

“…In a study by Qiu et al, diabetic model rats who were administered GYY4137 before myocardial ischemiareperfusion injury showed smaller infarcts, reduced apoptosis, and lower oxidative stress than the control group, implying that the protective effect of GYY4137 against myocardial ischemiareperfusion injury is linked to p-Akt and nuclear Nrf2 protein (73). In addition, Zheng et al employed GYY4137 to show that H 2 S molecules regulate the PI3K/Akt/TLR4 signaling pathway to stabilize vascular plaques (74). As research continues, the atherosclerotic potential of GYY4137 is increasingly being unraveled, such as prevention of vascular inflammation and oxidative stress (75), protection against myocardial fibrosis (18), and attenuation of adverse remodeling (76).…”