SERP1 Mediated The Vascular Restenosis Process By Regulating GLP-1 Receptor Glycosylation After Arterial Injury

ObjectiveThe increasing incidence of type 2 diabetes mellitus(T2DM)has been widely concerned by the WHO,and it has even become a serious economic burden all around the world.The vascular complications caused by T2 DM are a terrible threat to the health of these patients.Intravascular therapy is now regularly used for the treatment of diabetic macroangiopathy.Glucagon like peptide 1(GLP-1)and its receptor agonists are used to prevent the vascular restenosis after intravascular therapy,but the studies found the GLP-1 receptor(GLP-1R)dysfunction among diabetics will limit the efficacy of GLP-1R agonists and other related drugs.The purpose of this study is to explore the possible causes of dysfunction of GLP-1R on endothelial cells(ECs)and vascular smooth muscle cells(VSMCs)in diabetic patients,and explore ways to improve GLP-1R function among diabetics.MethodsRat aortic endothelial cells(RAOECs)and rat VSMCs were cultured in vitro with different concentrations of glucose.The levels of glycosylation of GLP-1R on two types of cell were detected by western blot.The binding of GLP-1R and stress-associated endoplasmic reticulum protein 1(SERP1)was detected by co-immunoprecipitation.The effects of exogenous SERP1 concentration on the GLP-1R glycosylation of two types of cell in high glucose were detected.The effects of different concentrations of exogenous GLP-1 on the level of phosphorylated eNOS in RAOECs and phosphorylated AMPK in VSMCs were measured under the action of exendin-4,a GLP-1 analogue.Flow cytometry was used to detect the effect of SERP1 on the proliferation of RAOECs.Cell scratch test and transwell were used to detect the effect of SERP1 on VSMCs migration.Based on the establishment of diabetic rats model,in in vitro experiments carotid artery ultrasound and immunohistochemistry were used to determine carotid artery intima-media thickness(IMT)and rat arterial stenosis in different groups of animal after 14 days later with.Evans blue and immunofluorescence were used to detect the re endothelialization of the carotid artery and the proliferation of VSMCs in rats' carotid artery.Results1.Hyperglycemia inhibits the N-Glycosylation of GLP-1R in RAOECs and VSMCs.2.SERP1 facilities the N-Glycosylation and activity of GLP-1R in RAOECs and VSMCs.3.SERP1 injection decreases the IMT in diabetic rats following carotid injury.4.SERP1 injection alleviates the neointimal hyperplasia by promoting the re-endothelialization and reducing the VSMCs proliferation in diabetic rats following carotid injury.ConclusionExogenous SERP1 plays an important role in the prevention of restenosis after interventional therapy in diabetic rats by improving the glycosylation of GLP-1R in RAOECs and VSMC.