SHP-2对Apo E基因敲除小鼠动脉粥样硬化斑块及其内部巨噬细胞表型的影响  

Effects of SHP-2 on atherosclerotic plaque and macrophage phenotype in Apo E knockout mice

作　　者：朱学灿 路永刚[2] 于悦卿[2] 霍丽静[2] 帖彦清[2] ZHU Xuecan;LU Yonggang;YU Yueqing;HUO Lijing;TIE Yanqing(Hebei North University,Zhangjiakou 075000,China)

机构地区：[1]河北北方学院,河北张家口075000 [2]河北省人民医院

出　　处：《山东医药》2018年第34期5-8,共4页Shandong Medical Journal

基　　金：河北省政府资助临床医学优秀人才培养和基础课题研究项目计划(361003)

摘　　要：目的观察磷酸酶SHP-2对Apo E基因敲除(Apo E^(-/-))小鼠动脉粥样硬化斑块及其内部巨噬细胞(M_φ)表型的影响。方法将Apo E^(-/-)小鼠(动脉粥样硬化模型小鼠)随机分为实验组和模型组各16只,均给予高脂饲料喂养,同时实验组腹腔注射溶于0.5%DMSO的SHP-2抑制剂PHPS1 3 mg/(kg·d),模型组腹腔注射等量0.5%DMSO,每天注射1次,共16周。用油红O和Movat染色分别评估主动脉整体和主动脉根部斑块面积,天狼星红、免疫组化染色分别检测主动脉根部斑块内胶原、M_φ(galectin-3/MAC-2阳性区域)和平滑肌细胞(β-actin阳性区域),应用实时荧光定量PCR法检测降主动脉中的M1型(i NOS、TNF-α和IL-6)和M2型(IL-10、Arg-1和FIZZ-1)M_φ标志性因子基因。结果实验组主动脉整体和主动脉根部斑块面积小于模型组,但差异无统计学意义。与模型组比较,实验组主动脉根部斑块内M_φ阳性区域减小(P<0.05),平滑肌细胞、胶原成分阳性区域增大(P均<0.05);降主动脉斑块内M1型M_φ标志性因子基因表达降低(P均<0.05),M2型M_φ标志性因子基因表达升高(P均<0.05)。结论磷酸酶SHP-2可抑制Apo E^(-/-)小鼠动脉粥样硬化斑块内M_φ向M2型分化,从而导致斑块不稳定性增加。Objective To investigate the effects of phosphatase SHP-2 on atherosclerotic plaque and macrophage （M φ） phenotype in Apo E knockout （Apo E -/- ） mice.Methods Sixteen C57 mice were randomly divided into the following two groups： the model group and the experimental group, and mice in both groups were fed with high-fat diet for sixteen weeks. At the same time, the mice in the experimental group were intraperitoneally injected with 0.5% PHPS1 3 mg/（ kg·d ）, a SHP-2 inhibitor dissolved in 0.5% DMSO, and the same amount of 0.5% DMSO was injected daily into the mice of the model group. The plaque area of aorta and aortic root was assessed by using oil red O and Movat staining. The plaque macrophages （galectin-3/MAC-2 positive area） and smooth muscle cell （β-actin positive area） of aortic root were detected by immunohistochemical staining. The plaque collagen of aortic root was detected by Sirius red staining. The expression of type M1 （iNOS, TNF-α, and IL-6） and type M2 （IL-10, Arg-1, and FIZZ-1） macrophage marker genes in the aorta and aortic root was detected by real-time fluorescent quantitative polymerase chain reaction.Results The plaque area of the aorta and aortic root in the experimental group was smaller than that in the model group, with no statistically significant difference. Compared with the model group, the positive area of Mφ in the aortic root plaque of the experimental group decreased, and the positive area of smooth muscle cells and collagen increased （ P 〈0.05）. In the descending aortic plaques, the expression of M1-type Mφ gene markers decreased and the expression of M2 type Mφ gene markers increased （both P 〈0.05）.Conclusion The phosphatase SHP-2 can inhibit the differentiation of Mφ to type M2 in plaque, which leads to the increase of plaque instability.

关 键 词：动脉粥样硬化 蛋白酪氨酸磷酸酶 SHP-2抑制剂 斑块稳定性 巨噬细胞表型 APO E基因敲除小鼠 

分 类 号：R543.1[医药卫生—心血管疾病]