ActRⅡA介导阿托伐他汀对动脉粥样硬化的治疗作用

Therapeutical effect of atorvastatin on artheroscleros mediated by ActRⅡA

目的:探讨激活素ⅡA型受体(ActRⅡA)在动脉粥样硬化(AS)斑块组织中的表达及其与阿托伐他汀干预治疗的关系,阐明阿托伐他汀对AS的治疗作用及可能的信号转导机制。方法:24只载脂蛋白E基因敲除(apoE-/-)小鼠随机分为空白对照组、高脂饮食组和高脂他汀组(每组8只),分别给予普通小鼠颗粒饮食、高脂饲料、高脂饲料+阿托伐他汀,饲养8周后,检测小鼠血清甘油三酯(TG)和总胆固醇(TC)水平,HE染色观察主动脉弓病理学变化,免疫组化染色观察并检测斑块内ActRⅡA的表达。结果:①高脂饮食组和高脂他汀组小鼠血清TG和TC水平及激活素ⅡA型受体(ActRⅡA)相对灰度值明显高于空白对照组(P<0.05),高脂他汀组小鼠血清TG和TC水平及ActRⅡA相对灰度值明显低于高脂饮食组(P<0.05)。②与空白对照组比较,高脂饮食组及高脂他汀组小鼠主动脉弓均可见明显AS斑块,但高脂他汀组AS斑块的内膜增厚,泡沫细胞含量极少且纤维帽较厚,斑块较稳定。③免疫组织化学染色,空白对照组小鼠主动脉弓标本ActRⅡA基本无表达,高脂饮食组小鼠AS斑块处可见密集的棕色及棕黄色颗粒,ActRⅡA呈强阳性表达。高脂他汀组小鼠AS斑块处可见分散的棕色及棕黄色颗粒,ActRⅡA表达明显低于高脂饮食组。结论:AS斑块内可检测到ActRⅡA表达,激活素可能通过ActRⅡA途径参与AS形成过程;他汀类药物能够显著降低TG和TC水平、降低斑块内ActRⅡA表达、稳定AS斑块,提示他汀类药物可能通过作用于ActRⅡA相关激活素信号转导途径而发挥抗炎及治疗AS作用。

Objective To detect the expression of activin receptorⅡA（ActRⅡA） in atherosclerosis（AS） plaque tissue and investigate the association between ActRⅡA and effect of statins,and to clarify the anti-inflammatory mechanisms and potential signal transduction pathway of statins.Methods 24 apoE-/-mices were randomly divided into control group,high fat diet group,high fat diet plus atorvastatin group,and they were separately given normal mouse forage,high fat diet,high fat diet plus atorvastatin.After 8 weeks,the serum triglyceride（TG） and total cholesterol（TC） were detected,the pathological changes of the aortic arch were observed by HE staining and the expression of ActRⅡA in atherosclerotic plaques was determined by immunohistochemical method.Results ①The serum TG and TC and the expression of ActRⅡA of mice in high fat diet group and high fat diet plus atorvastatin group were higher than those in control group（P0.05）,and they were decreased in high fat diet plus atorvastatin group compated with high fat diet group（P0.05）.②Compared with control group,the HE staining results showed obvious atherosclerotic plaques in aortic arch in high tat diet group and high fat diet plus atorvastatin group,but atherosclerotic plaque in high fat diet plus atorvastatin group had the thicken intima,rare foam cells and thicker fiber cap,the plaques were more stable.③The immunohistochemical assay showed little expression of ActRⅡA in control group,whereas ActRⅡA had obviously positive expressions in the other two groups.The expression of ActRⅡA in high fat diet plus atorvastatin group was lower than that in high fat diet group.Conclusion The expression of ActRⅡA could be detected in the plaques in this experiment,and ActRⅡA may be involved in the formation of AS.Statins could decrease the levels of TG,TC and expression of ActRⅡA in atherosclerotic plaque,suggested that statins may play their anti-inflammatory mechanisms by acting on ActRⅡA or its signal transduction pathway.