二甲双胍通过抑制缺氧诱导脂滴相关蛋白与卷曲蛋白10相互作用及其下游Wnt信号减缓腹主动脉瘤形成的研究  

Metformin attenuates abdominal aortic aneurysm formation by inhibition of HILPDA interaction with FZD10-mediated Wnt signaling

作　　者：田丽 张瑾瑾 张娜娜 马冬 TIAN Li;ZHANG Jinjin;ZHANG Nana(Department of Geriatrics,Tangshan Central Hospital,Tangshcm 063000,China)

机构地区：[1]唐山中心医院老年病科,063000 [2]华北理工大学公共卫生学院

出　　处：《中国糖尿病杂志》2022年第2期120-125,共6页Chinese Journal of Diabetes

基　　金：国家自然科学基金(81700416)。

摘　　要：目的探讨二甲双胍抑制腹主动脉瘤(AAA)形成的分子机制。方法构建高脂饲养ATⅡ灌注的ApoE-/-小鼠AAA模型20只,随机分为AAA组和二甲双胍干预组(Met),每组各10只。分离原代培养小鼠AAA血管壁外周脂肪细胞(PAs),油红O染色观察PAs形态和脂质含量,生物信息学预测、荧光染色、免疫共沉淀和免疫印迹证实与缺氧诱导脂滴相关蛋白(HILPDA)相互作用的分子和Wnt信号。结果与AAA组比较,Met组腹主动脉瘤体直径减少(P<0.01),PAs累积减少,PAs油红O染色阳性细胞比例降低(P<0.01),卷曲蛋白10(FZD10)、p-β-catenin/β-catenin和Cyclin D1蛋白表达降低(P<0.05或P<0.01)。在AAA中HILPDA与FZD10相互作用增强。结论二甲双胍通过抑制HILPDA与FZD10间的相互作用,调控Wnt信号的过度激活和PAs累积,有效减缓AAA形成。ObjectiveTo explore the molecular mechanism by which Metformin inhibiting the formation of abdominal aortic aneurysm(AAA).MethodsA total of 20 Apo E-/-AAA mice model was induced by perfusion of angiotensin II(AT II)with consumption of high-fat food.All mice were divided into AAA and Met groups on average.AAA and the corresponding adventitia adipose tissues,primary cultured perivascular adipocytes(PAs)were separated and cultured in vivo.Oil red staining was used to observe adipose tissue of the vascular adventitia as well as the morphology and lipid content of PAs.Bioinformatics predicts which protein interacts with hypoxia-induced lipid droplet-related proteins.Double immunofluorescence staining,co-immunoprecipitation and Western blot confirm the interaction between proteins and their downstream signal molecules.ResultsCompared with AAA group,the tumor diameter,PAs accumulation,the number of PAs oil red O-positive cells and the expression of FZD10,p-β-catenin/β-catenin and Cyclin D1 protein decreased in Met group(P<0.05 or P<0.01).During the formation of AAA,the interaction between the protein HILPDA and FZD10 was enhanced.ConclusionMetformin suppresses the interaction between HILPDA and FZD10,and then reduces to the excessive activation of Wnt signal and accumulation of PAs,there by mitigates the formation of AAA.

关 键 词：二甲双胍 腹主动脉瘤 血管壁外周脂肪细胞 缺氧诱导脂滴相关蛋白 WNT信号通路 

分 类 号：R965[医药卫生—药理学]