Objective To investigate the effects of TLR3 activator-poly (I ∶ C) on atherosclerotic plaque formation in ApoE-/-mice and its molecular mechanism.Methods A total of 10 specific pathogen free(SPF) male ApoE-/-mice were randomly divided into model group and poly (I ∶ C)group,with 5 mice in each group.The mice in model group and poly (I ∶ C) group were fed with high fat diet and high fat diet + poly (I ∶C),respectively,and the other five C57BL/6J mice fed with normal diet C57BL/6J were served as control group.After 14-week feeding,all the mice were sacrificed,then the body weight,fiber-cap thickness,vascular intima-media thickness,TC,TG,LDL-C,HDL-C,NO,MDA,SOD,IL-6,IL-1β,TNF-oα,VCAM-1,ICAM-1,P-selection and the expression levels of TLR3,TRIF,p-p38,p-JNK and p-ERK were observed and compared among the three groups.Results The body weight in model group was significantly higher than that in control group(P ＜ 0.05),but there was no significant difference in body weight between model group and poly(I ∶ C) group (P ＞ 0.05).No aortic plaque formation was found in control group,however,obvious aortic plaque formation and increase of vascular intima-media thickness were found in model group (P ＜ 0.05).As compared with those in model group,the aortic plaque formation and vascular intima-media thickness were significantly decreased in poly (I ∶ C) group (P ＜ 0.05).As compared with those in control group,the levels of TC,TG,LDL-C,MDA,IL-6,IL-1β,TNF-α,VCAM-1,ICAM-1,P-selection and the expression levels of TLR3,TRIF,p-p38,p-JNK,p-ERK proteins in model group were significantly increased,however,the levels of HDL-C,NO,SOD were significantly decreased (P ＜ 0.05).As compared with those in model group,the tevels of TC,TG,LDL-C,MDA,IL-6,IL-1β,TNF-α and the expression levels of VCAM-1,ICAM-1,P-selection,TLR3,TRIF,p-p38,p-JNK,p-ERK proteins were significantly decreased in poly (I ∶ C) group,however,the levels of HDL-C,NO and SOD were significantly increased (P ＜ 0.05).Conclusion TLR3 activator-poly (I ∶ C) can inhibit atherogenesis and relieve AS lesion in ApoE-/-mice by inhibiting the activation of TLR3/TRIF signal pathway and decreasing inflammatory factors release.%目的 观察TLR3激动剂poly(I∶C)对ApoE-/-小鼠动脉粥样硬化(AS)斑块形成的影响及相关分子机制.方法 10只SPF级雄性载脂蛋白E基因敲除(ApoE-/-)小鼠,随机分为模型组和poly(I∶C)组,每组5只.分别给予高脂饲料、高脂饲料+腹腔注射poly(I∶C)喂养.另设5只C57BL/6J小鼠为对照组,给予普通饲料喂养.给药14周后处死小鼠.比较3组体重、纤维帽厚度、血管内-中膜厚度、血清生化指标[总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-c)、高密度脂蛋白胆固醇(HDL-c)、一氧化氮(NO)、丙二醛(MDA)、超氧化物歧化酶(SOD)]、炎性因子[白介素6(IL-6)、白介素1β(IL-1β)、肿瘤坏死因子-α(TNF-α)]、黏附分子[血管细胞黏附因子-1(VCAM-1)、细胞间黏附分子-1(ICAM-1)、P-选择素(P-selection)]、Toll样受体3(TLR3)及其下游依赖β-干扰素TIR结构域衔接蛋白(TRIF)、磷酸化p38丝裂原活化蛋白激酶(p-p 38)、磷酸化c-jun氨基末端激酶(p-JNK)、磷酸化细胞外信号调节(p-ERK)蛋白表达变化.结果 模型组、poly(I∶C)组小鼠体重增加明显快于对照组(P＜0.05),但模型组、poly(I∶C)组间体重比较差异无统计学意义(P＞0.05).对照组主动脉管壁无斑块形成.模型组可见明显的主动脉斑块形成和血管内-中膜厚度增加(P＜0.05);与模型组比较,poly(I∶C)组纤维帽厚度、血管内-中膜厚度明显减小(P＜0.05).与对照组比较,模型组TC、TG、LDL-C、MDA、IL-6、IL-1β、TNF-α、VCAM-1、ICAM-1、P-selection、TLR3、TRIF、p-p38、p-JNK、p-ERK蛋白表达明显增加,HDL-C、NO、SOD明显降低(P＜0.05);与模型组比较,poly(I∶C)组TC、TG、LDL-C、MDA、IL-6、IL-1β、TNF-α、VCAM-1、ICAM-1、P-selection、TLR3、TRIF、p-p38、p-JNK、p-ERK蛋白表达明显降低,HDL-C、NO、SOD明显增加(P＜0.05).结论 TLR3激动剂poly(I∶C)通过抑制TLR3/TRIF信号通路的激活及炎症因子的释放减轻ApoE-/-小鼠AS病变.
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