Research Of Exenatide On Protective Effect Of Apolipoprotein E-knockout Mice Endothelial Function And Its Mechanism

Objective To investigate whether glucagon-like peptide-1(GLP-1)receptor agonist exenatide might improve the endothelial dysfunction of ApoE knockout mice and study its possible mechanism.Methods Wild-type(WT)C57BL/6 male mice and ApoE knockout mice of C57BL/6 background were randomly divided into four groups,Wild-type control group(WT),Wild-type treated group(WT+Ex-4),ApoE control group(ApoE)and ApoE treated group(ApoE+Ex-4).All mice were fed with high cholesterol diet.Exenatide treatment for 8 weeks.Endothelium-dependent vasodilatation of arteries and plasma lipids,glucose,insulin,nitric oxide levels were tested.Aortal expression of eNOS,p-eNOSser-1177,GTPCH-1 and BH4 levels were measured.Results Plasma NO levels markedly decreased in ApoE group,and maximum endothelium-dependent vasodilatation(EDV)value was severely reduced in this group.Exenatide treatment in ApoE-KO mice can significantly increase their NO level,improved endothelium-dependent vasodilatation,but has no effect on plasma lipids.And Exenatide also enhanced vascular protein expression of eNOS,phosphorylation of p-eNOSser-1177 and GTPCH-1,increased arterial BH4 content.Conclusion Exenatide can improve endothelial dysfunction.The protective mechanism is probably related to its effect of promoting GTPCH-1 protein expression,increasing BH4 level.Exenatide also help maintain normal function of eNOS,increased aortal phosphorylation of p-eNOSser-1177 levels and increased NO production,improved endothelium-dependent relaxation,and achieved the effect of vascular protection.