火把花根片通过调控NOD2/SMAD3/VEGFA信号通路干预类风湿关节炎血管内皮细胞功能紊乱的作用机制研究  

Investigation on the mechanisms of Colquhounia Root Tablets in reversing vascular endothelial cell dysfunction of rheumatoid arthritis via modulating NOD2/SMAD3/VEGFA signaling axis

作　　者：蔡冰冰 陈亚文 李涛[2] 曾源 张彦琼 林娜[2] 毛霞[2] 林雅[1] CAI Bing-bing;CHEN Ya-wen;LI Tao;ZENG Yuan;ZHANG Yan-qiong;LIN Na;MAO Xia;LIN Ya(College of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China;Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China)

机构地区：[1]福建中医药大学药学院,福建福州350122 [2]中国中医科学院中药研究所,北京100700

出　　处：《药学学报》2025年第2期397-407,共11页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金面上资助项目(82274176)。

摘　　要：类风湿关节炎(RA)是一种慢性难治性自身免疫病,主要表现为滑膜炎症和关节破坏。血管生成在RA的病理进程中起着关键作用,血管内皮细胞作为血管生成的核心参与者,其功能紊乱加速促进滑膜炎症,加剧血管翳的形成及关节破坏。中成药火把花根片临床上治疗RA效果显著,但其通过调控血管内皮细胞功能抑制RA血管生成的机制尚未明晰。本研究采用转录组学数据挖掘、生物网络分析与体内外实验验证相结合的研究策略,初步探讨了火把花根片抑制RA血管生成的潜在分子机制。动物福利和实验过程均遵循中国中医科学院中医基础理论研究所实验动物伦理委员会的规定(批准号:IBTCMCACMS21-2307-06)。网络分析结果表明核苷酸结合寡聚化结构域蛋白2(NOD2)、SMAD家族成员3(SMAD3)和血管内皮生长因子A(VEGFA)等核心基因显著富集于NOD样受体信号通路、VEGF信号通路等,提示火把花根片可能通过调控血管生成相关通路,影响血管内皮细胞功能,从而抑制血管生成。体内研究中火把花根片能显著下调佐剂诱导性关节炎(AIA)模型大鼠踝关节组织中血小板-内皮细胞黏附分子(CD31)和VEGF阳性表达。体外实验进一步验证,火把花根片可有效抑制由VEGF诱导的HUVEC细胞迁移、侵袭及管腔形成,显著降低血管生成相关因子VEGFA、CD31、血管生成素-1(Ang-1)的表达水平,减少HUVEC细胞中CD31、VEGF的阳性表达。同时,火把花根片还明显抑制NOD2、SMAD3、VEGFA等相关蛋白表达。综上,本研究揭示火把花根片通过靶向NOD2/SMAD3/VEGF信号轴改善血管内皮细胞功能,抑制RA异常血管生成的作用。上述研究丰富了中成药火把花根片在抑制RA病理性血管生成方面的科学内涵,也为临床防治类风湿关节炎提供新的思路。Rheumatoid arthritis(RA)is a chronic autoimmune disease characterized by synovial inflammation,joint destruction,and functional impairment.Angiogenesis plays a key role in the pathological progression of RA with dysfunction of endothelial cells to promote synovial inflammation,sustain pannus formation,subsequently leading to joint damage.Colquhounia Root Tablets(CRT),a Chinese patent drug,has shown a satisfying clinical efficacy in treating RA,while the underlying mechanism by which CRT inhibits RA-associated angiogenesis remains unclear.In this study,we applied a research approach combining transcriptomic data analysis,bio-network mapping,and in vivo and in vitro experiments to explore the molecular mechanisms of CRT in suppressing angiogenesis in RA.Animal welfare and experimental procedures follow the regulations of the Animal Ethics Committee of Institute of Basic Theory for Chinese Medicine,China Academy of Chinese Medical Sciences(ratification number:IBTCMCACMS21-2307-06).Network analysis identified that key genes such as nucleotidebinding oligomerization domain-containing protein 2(NOD2),SMAD family member 3(SMAD3),and vascular endothelial growth factor A(VEGFA)significantly enriched in pathways related to NOD-like receptor signaling and VEGF signaling,indicating that CRT may inhibit angiogenesis by regulating vascular endothelial cell function with modulating angiogenesis-related pathways.In vivo data showed that CRT significantly reduced the positive expression of CD31 and VEGF in the ankle joint of adjuvant-induced arthritis(AIA)rats.In vitro data further confirmed that CRT effectively inhibited VEGF-induced migration,invasion,and tube formation in HUVECs,while significantly reduced the expression of angiogenesis-related factors VEGF/CD31/Ang-1,as well as the positive expression of VEGF and CD31 in HUVECs.Furthermore,CRT markedly decreased the protein expression of NOD2,VEGFA,and SMAD3.In conclusion,these findings indicate that CRT may inhibit the RA-related angiogenesis by targeting the NOD2/SMAD3/VEGF

关 键 词：火把花根片 类风湿关节炎 血管生成 人脐静脉内皮细胞 血管内皮细胞功能紊乱 作用机制 

分 类 号：R966[医药卫生—药理学]