姜黄素通过激活NRF2-DDAH-ADMA-NO途径抑制内皮间质化改善心脏纤维化  

Curcumin improves cardiac fibrosis by inhibiting endothelial-mesenchymal transition through NRF2-DDAH-ADMA-NO pathway

作　　者：陈骁[1] 陈长曦[1] 高瞻[1] 陈星星[1] 胡杰[1] 周浩[1] CHEN Xiao;CHEN Chang-xi;GAO Zhan;CHEN Xing-xing;HU Jie;ZHOU Hao(Vasculocardiology,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou 325000,China)

机构地区：[1]温州医科大学附属第一医院心血管内科,浙江温州325000

出　　处：《中国中药杂志》2022年第3期745-752,共8页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(81873468)。

摘　　要：该研究以心脏纤维化SD大鼠为对象,分析姜黄素(curcumin,Cur)、核因子NF-E2相关因子(nuclear factor-E2-related factor 2,NRF2)-二甲基精氨酸二甲胺水解酶(dimethyl arginine dimethylamino hydrolase,DDAH)-非对称性二甲基精氨酸(asymmetric dimethyl arginine,ADMA)-一氧化氮(nitric oxide,NO)途径、内皮细胞-间质化(endothelial-mesenchymaltransition,EndMT)三者之间的关系,探讨Cur抗心脏纤维化的作用和机制,为其在心衰治疗上的临床应用提供更深入的理论依据。通过以异丙肾上腺素(isoprenaline,Iso)皮下注射构建大鼠心脏纤维化模型。实验过程中使用32只SD大鼠,按每组8只随机分为4组,即对照组、模型组(Iso)、低剂量Cur组(100 mg·kg^(-1)·d^(-1)Cur灌胃)、高剂量Cur组(200 mg·kg^(-1)·d^(-1)Cur灌胃)。给药21 d后心超检查心功能情况,Masson染色检查心肌纤维化程度,病理染色测定CD31和α-SMA表达,Western blot检测VE-cadherin、vimentin、NRF2、DDAH表达,HPLC检测ADMA水平等。与模型组相比,经Cur干预后大鼠心脏纤维化程度明显下降,并伴随着内皮细胞标志物CD31、VE-cadherin表达上调,间质细胞标志物α-SMA、vimentin下调,提示EndMT减轻。另外,与模型组相比,Cur组的DDAH和NRF2表达升高,ADMA、NO水平明显下降。综上所述,Cur有通过抑制EndMT起到抗心脏纤维化的作用,其作用机制可能为通过干预NRF2-DDAH-ADMA-NO途径来完成。The present study analyzed the correlations between curcumin(Cur),nuclear factor E2 related factor 2(NRF2)-dimethylarginine dimethylaminohydrolase(DDAH)-asymmetric dimethylarginine(ADMA)-nitric oxide(NO) pathway,and endothelial-mesenchymal transition(EndMT) based on SD rats with cardiac fibrosis,and explored the effect and mechanism of Cur in resisting cardiac fibrosis to provide an in-depth theoretical basis for its clinical application in the treatment of heart failure.The cardiac fibrosis model was induced by subcutaneous injection of isoprenaline(Iso) in rats.Thirty-two rats were randomly divided into a control group,a model group,a low-dose Cur group(100 mg·kg^(-1)·d^(-1)),and a high-dose Cur group(200 mg·kg^(-1)·d^(-1)),with eight in each group.After 21 days of treatment,cardiac function was detected by echocardiography,degree of cardiac fibrosis by Masson staining,expression of CD31 and α-SMA by pathological staining,expression of VE-cadherin,vimentin,NRF2,and DDAH by Western blot,and ADMA level by HPLC.Compared with the model group,the Cur groups showed alleviated cardiac fibrosis,accompanied by increased CD31 and VE-cadherin expression and decreased α-SMA and vimentin expression,indicating relieved EndMT.Additionally,DDAH and NRF2 levels were elevated and ADMA and NO expression declined.Cur improves cardiac fibrosis by inhibiting EndMT presumedly through the NRF2-DDAH-ADMA-NO pathway.

关 键 词：内皮间质化 姜黄素 非对称性二甲基精氨酸 二甲基精氨酸二甲胺水解酶 核因子NF-E2相关因子 

分 类 号：R285[医药卫生—中药学]