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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

Objective To study the association of apolipoprotein E ( APOE ) gene polymorphism with ischemic stroke (IS) in coronary heart disease (CHD) patients treated with medium-intensity statins. Methods The retrospective study was performed on 662 samples including 169 CHD subjects complicated with IS, 296 subjects with CHD, and 197 control subjects. The APOE gene was obtained from case files. Univariable and multivariable logistic regression analyses were utilized to recognize the possible risks of CHD and IS. Results The frequency of ε3-ε4 genotype was increased in the CHD group ( p =0.013) and CHD-IS group ( p =0.001), the frequency of ε4 allele was also increased in the CHD group ( p =0.047) and the CHD-IS group ( p =0.009) compared with control group. ε3-ε4 genotype was the independent risk for CHD and CHD-IS after adjusting for traditional risk factors with adjusted odds ratio (AOR) 2.210, 95%CI: 1.263–3.867, p =0.005) and (AOR 2.794, 95%CI: 1.539–5.072, p =0.002). The ε4 allele was also significantly associated with CHD (AOR 2.126, 95%CI: 1.265–3.575,=0.004) and CHD-IS (AOR 2.740, 95%CI: 1.569–4.784, p =0.001). Conclusion These results demonstrated that ε4 allele influenced the development of CHD with or without IS, especially for the genotype of ε3-ε4. CHD patients carrying the ε3-ε4 genotype and the ε4 allele were significantly associated with the incidence of IS, even if medium-intensity statins had been used.

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Background Diabetes is considered to be a high-risk factor for thromboembolic events. However, available data about the optimal dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) after second-generation drug-eluting stent (DES) implantation are scant. Objective The purpose of this study was to compare the impact of various DAPT durations on clinical outcomes in patients with DM after second-generation DES implantation. Methods We searched PubMed, Embase, and the Cochrane Library for studies that compared short-term (≤ 6 months) and long-term (≥ 12 months) DAPT in patients with DM. The primary endpoints were late (31–365 days) and very late (> 365 days) stent thrombosis (ST). The secondary endpoints included myocardial infarction (MI), target vessel recanalization (TVR), all-cause death, and major bleeding. Results Six randomized controlled trials, with a total of 3,657 patients with DM, were included in the study. In terms of the primary endpoint, there was no significant difference between the two groups in late (OR 1.15, 95% CI: 0.42–3.19, P = 0.79) or very late (OR 2.18, 95% CI: 0.20–24.18; P = 0.53) ST. Moreover, there was no significant difference in the secondary endpoints, including MI (OR 1.11, 95% CI: 0.72–1.71, P = 0.63), TVR (OR 1.31, 95% CI: 0.82–2.07, P = 0.26), all-cause death (OR 1.03, 95% CI: 0.61–1.75, P = 0.90) and major bleeding (OR 1.07, 95% CI: 0.34–3.40, P = 0.90) between the two groups. Conclusion Our study demonstrated that compared with long-term DAPT, short-term DAPT had no significant difference in the clinical outcomes of patients with DM implanted with second-generation DES.