HDAC3抑制剂RGFP966通过下调TGF-β1/SMAD3/STAT-1信号通路抑制AIM2炎症小体活化和EMT缓解子宫内膜纤维化  

HDAC3 Inhibitor RGFP966 Alleviates Endometrial Fibrosis by Regulation of AIM2 Inflammasome and EMT through TGF-β1/SMAD3/STAT-1 Signaling Pathway

作　　者：卢建军[1] 张新悦 LU Jianjun;ZHANG Xinyue(Department of Obstetrics and Gynaecology,Inner Mongolia Medical University Affiliated Hospital,Hohhot,010059,China)

机构地区：[1]内蒙古医科大学附属医院妇产科,呼和浩特市010059

出　　处：《医学分子生物学杂志》2024年第3期211-216,共6页Journal of Medical Molecular Biology

基　　金：中央引导地方科技发展资金(No.2022ZY0186)。

摘　　要：目的探讨HDAC3抑制剂RGFP966缓解子宫内膜纤维化的分子机制。方法将18只6~8周雌性SD大鼠随机分为3组,Control组、IUA模型组(即宫内粘连大鼠模型组)、RGFP966治疗组(IUA模型组给予HDAC3抑制剂RGFP966治疗),每组6只。建立IUA大鼠模型。ELISA测定大鼠血清炎症因子TNF-α、IL-1β和IL-6水平。qPCR法测定大鼠子宫内膜组织上皮间质转化标志物E-cadherin、N-cadherin、α-SMA、Vimentin mRNA相对表达水平。蛋白质印迹法测定大鼠子宫内膜组织TGF-β1、SMAD3、p-STAT-1、STAT-1、AIM2、IL-18、cleaved-IL-1β、IL-1β的表达水平。结果与Control组相比,IUA模型组大鼠子宫角壁变薄,血清炎症因子TNF-α、IL-1β、IL-6水平升高(P<0.05);E-cadherin mRNA相对表达水平降低,N-cadherin、α-SMA、Vimentin mRNA相对表达水平升高(P<0.05);TGF-β1、SMAD3、p-STAT-1蛋白质表达水平增强(P<0.05);AIM2、IL-18、cleaved-IL-1β的表达水平增强(P<0.05)。与IUA模型组相比,RGFP966治疗组部分逆转(P<0.05)了上述指标。STAT-1和IL-1β的表达水平在上述3个分组中无明显差异(P>0.05)。结论HDAC3的抑制剂RGFP966可通过下调TGF-β1/SMAD3/STAT-1信号通路抑制AIM2炎症小体和EMT,缓解子宫内膜纤维化。Objective To investigate the molecular mechanisms of HDAC3 inhibitor RGFP966 in alleviating endometrial fibrosis.Methods A total of 18 female SD rats(6-8 weeks)were randomly divided into 3 groups:Control group,IUA Model group(intrauterine adhesion rat Model),and RGFP966 Treatment group(IUA model group rats were treated with HDAC3 inhibitor RGFP966),with 6 rats in each group.IUA rat model was established.ELISA was used to determine the levels of the serum inflammatory cytokines TNF-α,IL-1βand IL-6.qPCR was used to determine the relative mRNA expression levels of EMT markers E-cadherin,N-cadherin,α-SMA and Vimentin.Western blotting was used to determine the protein expression levels of TGF-β1,SMAD3,phosphorylated STAT-1,STAT-1,AIM2,IL-18,cleaved IL-1βand IL-1β.Results The walls of uterine horn in the IUA Model group were thinner,the levels of serum inflammatory cytokines TNF-α,IL-1βand IL-6 were increased when compared with those in the Control group(P<0.05).The relative expression levels of Ecadherin mRNA were decreased,while the relative expression levels of N-cadherin,α-SMA and Vimentin mRNA were increased(P<0.05).The expression levels of TGF-β1,SMAD3,p-STAT-1 were enhanced(P<0.05).And the expression levels of AIM2,IL-18,cleaved IL-1βwere increased(P<0.05).The above indicators were partially reversed in RGFP966 Treatment group when compared with those in the IUA Model group(P<0.05).No significant differences in the expression levels of STAT-1 and IL-1βwere seen among the three groups(P>0.05).Conclusion HDAC3 inhibitor RGFP966 can alleviate endometrial fibrosis by down-regulating TGF-β1/SMAD3/STAT-1 signaling pathway to inhibit AIM2 inflammasome activation and EMT.

关 键 词：子宫内膜纤维化 宫内粘连 HDAC3抑制剂RGFP966 TGF-β1/SMAD3/STAT-1信号通路 AIM2炎症小体 

分 类 号：R711[医药卫生—妇产科学] R-332[医药卫生—临床医学]