Sitagliptin Attenuates Endothelial Dysfunction Induced By High-glucose Through Suppressing Autophagy

Purpose The prevalence of diabetes mellitus is increasing year by year,among which macrovascular complications are the main cause of death and disability.The impairment of vascular endothelial function caused by high glucose is the pathological basis of macrovascular complications.Sitagliptin is a kind of new drug for treating diabetes.Although the contributions of sitagliptin to endothelial dysfunction in diabetes mellitus were previously reported,the potential mechanisms still remain undefined.Autophagy is one of the research hotspots in recent years.It plays an important role in the development of diabetes mellitus and its complications,but its role in diabetic macrovascular complications is not clear.Our research was intended to observe the effects of sitagliptin on diabetic rats and human umbilical vein endothelial cells cultured in high glucose,and explore the role of autophagy in this process.Methods Experimental diabetes rats were induced through administration with combination of high-fat diet and intraperitoneal injection of streptozotocin.Rats were randomly divided into three groups,including controls,diabetes,diabetes+sitagliptin.Rats in sitagliptin group were given sitagliptin(10 mg/kg/day)by gavage for 12 weeks,while rats in control group and diabetes group were given an equal volume of saline.Blood glucose and body weight were monitored during the intervention.At the end of the intervention,inferior vena cava blood and aortic specimens were taken.Serum blood glucose,lipids files and VCAM-1 levels were measured.Morphological changes of aorta were observed;apoptosis of aortic endothelial cells was detected by TUNEL;expression of LC3?,JNK,Bcl-2,Beclin-1 protein in aortic tissues were detected by immunohistochemistry and/or western blot.In vitro experiment,human umbilical vein endothelial cells were cultured with high glucose and intervened with different concentrations of sitagliptin.Cell viability,the level of apoptosis and autophagy were measured.Then chose the appropriate concentration of sitagliptin and pretreated cells with rapamycin to activate autophagy,observed the change of cell viability,and measured the expression of LC3?,Bcl-2 and Beclin-1 protein.T-test was used to compare the means of two groups,and one-way ANOVA test was used to compare the means of multiple groups.Results Vascular endothelial cells were damaged in diabetic rats.Sitagliptin could attenuate vascular endothelial dysfunction in diabetic rats.The level of autophagy in aorta tissues of diabetic rats was increased,and sitagliptin could decrease the level of autophagy.And in this process,the expression of proteins in JNK-Bcl-2-Beclin-1 pathway was changed.In vitro,we found the viability of human umbilical vein endothelial cells cultured with high glucose was decreased,the level of apoptosis was increased,and autophagy was over-actived.Sitagliptin could dose-dependently improve the activity of high-glucose cultured human umbilical vein endothelial cells,reduce apoptosis and suppress autophagy.After pretreatment with rapamycin,the protective effect of sitagliptin was abolished.Conclusions High glucose can induce over-activation of autophagy in vascular endothelial cells.Sitagliptin can improve the injury of vascular endothelial cells in vivo and in vitro by inhibiting autophagy.JNK-Bcl-2-Beclin-1 pathway may be an intervention target of sitagliptin to protect endothelial cells through regulating apoptosis and autophagy.