别嘌醇及非布司他对家兔快速心房起搏房颤模型心房结构重构的影响  

Effects of allopurinol and febuxostat on atrial structural remodeling in a rabbit model of atrial fibrillation induced by rapid atrial pacing

作　　者：凡永艳 彭建军 薛桥[2] 王玉堂[3] 李泱[2] FAN Yong-yan;PENG Jian-jun;XUE Qiao;WANG Yu-tang;LI Yang(Department of Cardiology,Beijing Shijitan Hospital of Capital Medical University,Beijing 100038,China;Department of Cardiology,The First Medical Center,Chinese PLA General Hospital,Beijing 100853,China;Department of Cardiology,The Second Medical Center,Chinese PLA General Hospital,Beijing 100853,China)

机构地区：[1]首都医科大学附属北京世纪坛医院心血管内科,北京100038 [2]解放军总医院第一医学中心心血管内科,北京100853 [3]解放军总医院第二医学中心心血管内科,北京100853

出　　处：《中国医药生物技术》2024年第4期315-324,共10页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(82370327);国家重点研发计划(2022YFA1104303-2)。

摘　　要：目的探讨黄嘌呤氧化酶(XO)抑制剂(别嘌醇及非布司他)对家兔快速心房起搏(RAP)房颤模型心房结构重构的影响。方法24只健康雄性新西兰白兔,随机分为4组:假手术组(S组)、快速心房起搏组(P组)、快速心房起搏-别嘌醇干预组(ALL组)及快速心房起搏-非布司他干预组(FP组)。4周的RAP后行经胸超声心动图检查,同时对左心房心肌组织进行HE染色、Masson染色,并进行透射电子显微镜观察。qRT-PCR及Western blot检测TGF-β1、Smad7、Collagen I及α-SMA的mRNA和蛋白表达。结果P组的LAD、LAVmax及LAVmin均显著高于S组(P<0.01),LAEF显著低于S组(P<0.01);FP组的LAD显著低于ALL组(P<0.01),而两组LAVmax、LAVmin、LAEF之间的比较不具有统计学差异(P>0.05)。RAP导致左心房心肌组织出现严重的病理性损伤,并导致心房肌细胞超微结构发生改变,应用XO抑制剂干预(尤其是非布司他)可以减轻这些异常的病理改变,同时减轻左心房组织超微结构的损伤。P组左心房纤维组织面积的比例明显高于S组(P<0.01);应用XO抑制剂干预后纤维组织面积的比例与P组相比均明显降低(P<0.01),且FP组明显低于ALL组(P<0.05)。RAP导致TGF-β1 mRNA和蛋白表达显著增加,Smad7 mRNA和蛋白表达显著降低,同时上调Collagen I和α-SMA mRNA和蛋白表达水平;应用XO抑制剂干预可使TGF-β1、Collagen I和α-SMA mRNA和蛋白表达水平在一定程度上降低,同时上调Smad7 mRNA和蛋白表达,在FP组尤为明显。结论与别嘌醇相比,非布司他的干预显著改善了RAP诱导的心房结构重构,减轻了心房纤维化。Objective To evaluate the effects of xanthine oxidase(XO)inhibitors(allopurinol and febuxostat)on atrial structural remodeling in a rabbit model of atrial fibrillation induced by rapid atrial pacing(RAP).Methods Twenty-four rabbits were randomly divided into four groups:the sham-operated group(group S),RAP group(group P),RAP plus 50 mg/(kg·d)allopurinol group(group ALL),and RAP plus 10 mg/(kg·d)febuxostat group(group FP).Transthoracic echocardiographic examinations were performed after 4 weeks of RAP to evaluate the structure and function of the left atrium.Atrial histological changes were evaluated by HE staining.Masson's trichrome staining was used to evaluate atrial interstitial fibrosis.Transmission electron microscopy was used to evaluate changes in atrial ultrastructure.The expression levels of TGF-β1,Smad7,collagen I andα-SMA were measured by quantitative real-time PCR and Western blot.Results The LAD,LAVmax,and LAVmin were significantly increased in group P compared to group S(P<0.01),and the LAEF was dramatically decreased(P<0.01).Moreover,there was a decrease in the LAD after 4 weeks of RAP in group FP compared to group ALL(P<0.01),and there were no significant differences in the LAVmax,LAVmin or LAEF(P>0.05).RAP resulted in severe pathological damage and ultrastructural impairment in left atrial tissue,and these changes were reversed by the XO inhibitors,especially febuxostat.The proportion of fibrous tissue area in group P was significantly higher than in group S(P<0.01),and this effect was partially suppressed by XO inhibitors,especially in group FP(P<0.05).The mRNA and protein levels of TGF-β1,collagen I andα-SMA were significantly increased in group P compared to group S.However,XO inhibitors significantly suppressed these changes at both the mRNA and protein levels compared to those in group P,especially in group FP.Furthermore,RAP significantly decreased the expression of Smad7 in group P compared to group S.In contrast,the mRNA and protein levels of Smad7 were higher in the XO inhibitor-tr

关 键 词：心房颤动 心房结构重构 黄嘌呤氧化酶 非布司他 

分 类 号：R541.75[医药卫生—心血管疾病]