Effects Of Simvastatin On The Vascular Endothelial Dysfunction In Streptozotocin-induced Diabetic Rat And Its Underlying Mechanism

ObjectiveThis study was designed to observe the changes in vascular endothelial function of streptozotocin(STZ)induced diabetic(DM)rats and further study the protective effect of simvastatin on vascular endothelial dysfunction in diabetic rats and its possible mechanism.Significance: This study explores the relationshipbetween vascular endothelial dysfunction and inflammation and oxidative stress caused by DM,providing a theoretical basis for the prevention and reduction of cardiovascular diseases.It also provides experimental evidence for simvastatin in preventing and treating diabetic vascular dysfunction.Methods30 male SD rats were provided by the Experimental Animal Center of Jinzhou Medical University.The rats in model group and simvastatin group were injected STZ(50mg/kg)intraperitoneally for 5 days.5 days after 8 hours of fasting,the blood was collected from by the inner canthus vein and the glucose was measured.The blood glucose value of more than 15 mmol/L was considered to be a successful model of diabetic rats with a successful rate of80%.The rats were randomly divided into 2 groups with 12 rats in each group:the model group and the simvastatin group(20 mg/kg/d).Another 12 male SDrats were used as blank control group,Simvastatin was dissolved with 0.5%sodium carboxymethyl cellulose(CMC),and then administered by gavage to rats for 12 weeks.The blank control group and the model group were given the same volume of CMC daily.Index measurement methods: 1)weight was measured by electronic balance;2)the content of GLU,TC and TG in serum was measured by the commercial kit;3)vascular function was tested using the isolated aorta;4)frozen section was used to detect active oxygen in the aorta tissue by DHE staining;5)the concentration of TNF-? and IL-6 in serum was determined by ELISA method;6)western-blot was used to detect the protein expression of eNOS,tumor necrosis factor ?(TNF-?),interleukin 6(IL-6),Calpain-1,ICAM-1 and VCAM-1;7)immunohistochemical detection was used to determine the expression of ICAM-1 and VCAM-1;8)histomorphological study was undergone with HE staining and DHE staining.ResultsCompared with the blank control group,the weight of the rats in the model group decreased(P<0.05),the content of GLU,TC and TG in the serum increased(P<0.05),the vasodilatation function weakened(P<0.01),the reactive oxygen species in the blood vessels increased(P<0.05),the expression of eNOS protein in the vascular tissue decreased(P<0.05),the expression of Calpain-1 protein increased(P<0.05),and the expression of the protein expression of the inflammatory factors IL-6 and TNF-? in the vascular tissue was increased(P<0.05).In addition,the expression of intercellular adhesion molecules ICAM-1 and VCAM-1 detected by western blot in model group increased(P<0.05,P<0.01).The expression of ICAM-1 and VCAM-1 in the vascular intima was also increased detected by immunohistochemistry.HE staining and DHE staining showed that the morphological changes of vasculartissue in model group were obviously changed and the concentration of TNF-?and IL-6 in serum was increased(P<0.01,P<0.05).Compared with the model group,simvastatin can increase the weight of rats(P<0.05),reduce the content of GLU,TC and TG in serum(P<0.05),improve vasodilatation(P<0.05),reduce reactive oxygen in vascular tissue(P<0.05),increase the expression of eNOS protein in vascular tissue(P<0.05),decrease the expression of Calpain-1protein(P<0.05),and reduce the expression of inflammatory factors IL-6 and TNF-? in vascular tissue(P<0.05).Simvastatin also reduces the protein expression of intercellular adhesion molecule ICAM-1 and VCAM-1(P<0.05,P<0.01).In addition,simvastatin can decrease the expression of ICAM-1 and VCAM-1 in vascular intima,improve the morphological changes of vascular tissue,and reduce the concentration of TNF-? and IL-6 in serum(P<0.05).Conclusion1.Simvastatin inhibits the expression of Calpain1,decreases the expression of TNF-? and L-6,and reduces the expression of ICAM-1 and VCAM-1,and subsequently improving endothelial dysfunction in STZ-induced diabetic rats.2.Simvastatin inhibits the expression of Calpain1,increase the expression of eNOS,increase the production of NO and reduce the production of ROS,and subsequently alleviating the endothelial dysfunction of STZ-induced diabetic rats.