The Role Of Protein Tyrosine Phosphatase SHP-2 In The Formation Of Atherosclerosis In ApoE Knockout Mice

Atherosclerosis(AS),which causes myocardial infarction and stroke worldwide,is still the main cause of death in human beings.AS is a very complex chronic inflammatory process and also a key link in many diseases.In the process of AS development,vascular endothelial injury,macrophage recruitment,and immune cell interaction promote the chronic process of AS.Protein tyrosine phosphatase 2(SHP-2)is a protein expressed in various tissues of the body and has important physiological significance.PHPS1 is a specific inhibitor of SHP-2,which can effectively inhibit the phosphorylation of tyrosine phosphatase and hinder its role in signal transduction.The role of the two in atherosclerosis has not been seen in China.Report.What is the relationship between SHP-2 and atherosclerosis?What is the relationship between immune cells and AS?With these questions,our research group launched the following experiment.ApoE knockout mice were randomly divided into model group(control group)and experimental group(PHPS1 group).They were fed with high-fat diet to construct atherosclerosis model mice.During the feeding period,the experimental group was intraperitoneally injected with PHPS1(1mg/kg/d),a SHP-2 inhibitor,and the control group was given the same dose of normal saline.After 16 weeks of continuous feeding,the mice were killed.Oil red O staining was used to evaluate the area of aortic plaque in mice.The expression of T lymphocyte markers in spleen of mice was detected by flow cytometry.The expression of IFN-γ,IL-4 and IL-1βin serum were measured by ELISA.The area of aortic plaque core necrosis,the expression of smooth muscle cells(α-SMA)and macrophage markers(CD68,CD206,i NOS)were detected by movat staining,immunohistochemistry and immunofluorescence staining.Western blot technique was used to verify the expression of markers after phenotype transformation of macrophages in aorta.RT-PCR was used to detect the expression of macrophage markers in the aorta.The results showed that the oil red O staining showed that the experimental group was larger than that of the control group(P<0.05).In the experimental group,the expression of IFN-γ~+Th1 cells was increased,and the expression of IL-4~+Th2 cells was decreased(P<0.05).The expression of IFN-γand IL-1βin the serum of the experimental group was significantly higher than that of the control group(P<0.05 or 0.01),while the content of IL-4 was significantly lower than that of the control group(P<0.05).The area of necrotic core of aortic root plaque in the experimental group was increased(P<0.05),the positive area of macrophage in the plaque was more than that in the control group(P<0.05),the fluorescence intensity of M1 macrophage marker was higher than that of the control group,and the M2 macrophage marker was higher in the experimental group The results showed that the fluorescence intensity was lower than that of the control group(P<0.05).The expression of i NOS and IFN-γin the experimental group was higher than that in the control group(P<0.05).The expression of M1 type macrophage markers i NOS and IFN-γ,and the expression of M2macrophage markers CD206 and CD163.The relative expression of M1cell marker m RNA in aortic plaque of experimental group was increased,and the relative expression of M2 cell marker was decreased(P<0.05).The results showed that SHP-2 inhibitor PHPS1 could regulate T lymphocytes,promote T lymphocytes to transform into Th1 type cells,and promote the secretion of pro-inflammatory factors such as IFN-γ,enhance the activation of macrophages,accelerate the phenotypic transformation of macrophages,increase the polarization of macrophages,and promote the transformation of M1 type macrophages,so as to promote the development of atherosclerosis.