SHP-2抑制剂PHPS1对动脉粥样硬化斑块作用及其机制的研究

Study on the mechanism of SHP-2 inhibitor PHPS1 on atherosclerotic plaque

目的探讨蛋白酪氨酸磷酸酶SHP-2抑制剂PHPS1对ApoE基因敲除小鼠动脉粥样硬化斑块易损性的作用及其机理,为研究动脉粥样硬化提供新思路。方法16只8周龄ApoE^(-/-)小鼠随机分为对照组和PHPS 1组,给予西方膳食饲料16周,构建易损AS模型。取主动脉根部经福尔马林固定后制成切片,行Movat、天狼星红等染色法评估斑块内胶原、巨噬细胞含量等;降主动脉做Western blot检测ERK活性及基质金属蛋白酶-9(MMP-9)的表达量。结果PHPS1组和对照组相比主动脉根部动脉斑块面积大小(0.52±0.05)、(0.31±0.03)、斑块内胶原含量(0.062±0.013)、(0.136±0.022)及巨噬细胞细胞比例(0.799±0.031)、(0.621±0.043)有差异(P<0.01),同时斑块内MMP-9含量下降;Western blot结果显示PHPS1抑制了斑块内ERK活性,降低了MMP-9的蛋白表达量(P<0.01)。结论SHP-2抑制剂PHPS1通过抑制ERK活性,降低MMP-9的表达量,从而减少了纤维帽胶原成分的降解,进而稳定了易损动脉粥样硬化斑块。

Objective To investigate the effect and mechanism of Src homology 2 domain-containing protein tyrosine phosphatase inhibitor PHPS1 on atherosclerotic plaque vulnerability in ApoE knockout mice,and to provide anew idea for the study of atherosclerosis.Methods Sixteen 8-week-old ApoE^(-/-)mice were randomly divided into control group and PHPS1 group.The aortic root was fixed with formalin and sectioned.The collagen and macrophage contents in the plaque were evaluated by Movat and Sirius red staining.The activity of ERK and the expression of MMP-9 in the descending aorta were detected by Western blot.Results The plaque area(0.52±0.05),(0.31±0.03),collagen content(0.062±0.013),(0.136±0.022)and macrophage cell ratio(0.799±0.031),(0.621±0.043)were different between PHPS1 group and control group(P<0.01).The results of western blot showed that PHPS1 inhibited the activity of ERK and decreased the protein expression of MMP-9(P<0.01).Conclusion PHPS 1,an inhibitor of SHP-2,can inhibit ERK activity and decrease the expression of MMP-9,thus reducing the degradation of collagen in fibrous cap and stabilizing vulnerable atherosclerotic plaque.