目的 基于网络药理学和实验验证探讨雷公藤红素抗血管重塑的潜在靶点和作用机制。方法 通过SwissTargetPrediction、PharmMapper数据库筛选出雷公藤红素作用靶点。采用NCBI Gene、GeneCards及OMIM数据库预测血管重塑相关靶点，聚焦共同靶标，借助Cytoscape 3.8.1及STRING数据库构建蛋白质-蛋白质相互作用（protein-protein interaction，PPI）并筛选核心靶点。通过构建体外血管平滑肌细胞（vascular smooth muscle cells，VSMCs）增殖模型和小鼠股动脉拉伤模型，考察雷公藤红素对VSMCs增殖、促炎细胞因子水平及关键靶点表达的影响。结果 共获得雷公藤红素靶点56个，血管重塑靶点737个，药物疾病共同靶点20个，核心靶点有细胞周期蛋白D1（cyclin D1）、原癌基因c-Myc、核苷酸结合寡聚化结构域样受体蛋白3（nucleotide-binding oligomerization domain-like receptor protein 3，NLRP3）等。体外细胞实验表明，雷公藤红素显著抑制A7r5血管平滑肌细胞增殖能力（P<0.01），显著下调cyclin D1、c-Myc、NLRP3和半胱氨酸天冬氨酸蛋白酶-1（cystein-asparate protease-1，Caspase-1）的蛋白表达（P<0.05、0.01）。动物实验结果显示，雷公藤红素显著抑制股动脉拉伤小鼠模型股动脉NLRP3和Caspase-1的蛋白表达水平（P<0.01、0.001），降低血清中白细胞介素-6（interleukin-6，IL-6）和IL-1β水平（P<0.01、0.001）。结论 雷公藤红素可抑制VSMCs增殖，减轻损伤血管的重塑，其作用机制可能与改善血管炎症有关。

Objective To explore the potential targets and mechanism of celastrol against vascular remodeling through network pharmacology and experimental verification.Methods The targets of celastrol were mined by SwissTargetPrediction, Pharmmapper databases, and then the targets related to vascular remodeling were predicted by NCBI Gene, Genecards and OMIM databases. Protein-protein interaction (PPI) network was constructed to take the common targets of them, visualize and search core targets by Cytoscape 3.8.1 software and STRING database. The effects of celastrol on vascular smooth muscle cells (VSMCs) proliferation, levels of pro-inflammatory cytokines and expressions of core targets were investigated by constructing VSMCs proliferation models in vitro and a mouse model with femoral artery strain. Results A total of 56 targets of celastrol and 737 targets related to vascular remodeling were obtained, and 20 cross targets between celastrol and vascular remodeling were obtained. Key targets such as cyclin D1, proto-oncogene c-Myc, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) were obtained. In vitro cell experiments showed that celastrol significantly inhibited the proliferation of A7r5 cells (P < 0.01), significantly down-regulated the protein expressions of cyclin D1, c-Myc, NLRP3 and cystein-asparate protease-1 (Caspase-1) (P < 0.05, 0.01). Animal experiment results showed that celastrol significantly inhibited the protein expressions of NLRP3 and Caspase-1 in femoral artery of mice with femoral artery strain (P < 0.01, 0.001), decreased the levels of interleukin-6 (IL-6) and IL-1β in serum (P < 0.01, 0.001). Conclusion Celastrol can inhibit the proliferation of VSMCs and reduce the remodeling of injured vessels, and its mechanism may be related to the amelioration of vascular inflammation.

R285.5

国家自然科学基金项目面上项目（82274159）；国家自然科学基金项目面上项目（81973668）；国家自然科学基金项目面上项目（81774130）；湖南省自然科学基金科药联合基金资助项目（2022JJ80088）；湖南省教育厅项目（20A375，22B0355）；湖南省卫生健康委员会重点指导课题（202213055529）；长沙市科技局科研项目（No.kq2004060）；中药粉体与创新药物省部共建国家重点实验室培育基地开放基金项目（21PTKF1004）；湖南中医药大学研究生创新课题立项项目（2022CX76）