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.
Effects of allopurinol and febuxostat on atrial structural remodeling in a rabbit model of atrial fibrillation induced by rapid atrial pacing
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 and α-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 and α-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-treated groups than in group P,especially in the febuxostat group.Conclusion Compared to allopurinol,febuxostat significantly ameliorates RAP-induced atrial fibrosis and atrial structural remodeling.
万方数据
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