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田丰铭,佘瑞宁,蔺晓源,胡国恒.基于网络药理学探究祛瘀平肝化痰汤降压作用机制及实验验证[J].湖南中医药大学学报英文版,2022,42(3):410-417.[Click to copy
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| 基于网络药理学探究祛瘀平肝化痰汤降压作用机制及实验验证 |
| 田丰铭,佘瑞宁,蔺晓源,胡国恒 |
| (湖南中医药大学, 湖南 长沙 410208;湖南中医药大学第一附属医院, 湖南 长沙 410007) |
| 摘要: |
| 目的 运用网络药理学探讨祛瘀平肝化痰汤治疗高血压病的可能靶点及作用机制，并选取部分关键靶点及通路进行实验验证，为其临床应用及后续研究提供理论支持。方法 运用TCMSP、BATMAN、TCMIP网络药理学分析平台挖掘祛瘀平肝化痰汤的中药有效成分，运用SWISS、STITCH数据库整理其作用靶标；以OMIM、TTD、GeneCards数据库挖掘高血压病的相关靶标并与药物成分靶标取交集，整理后得到祛瘀平肝化痰汤的成分-疾病靶标；通过STRING数据库及Cytoscape软件，构建蛋白互作的网络图，并筛选关键靶点；最后将所得的靶标及通路进行富集分析。依据网络药理学所得结果，设置4组SD大鼠进行实验验证，包括空白组、模型组、中药组、西药组。除空白组外，其余组以N’-硝基-L-精氨酸（N'-nitro-L-arginine, L-NNA）腹腔注射进行造模。空白组与模型组予纯净水灌胃，中药组予祛瘀平肝化痰汤20.29 g/kg，西药组予卡托普利混悬液2.11 mg/kg，每天灌胃2次，连续4周。HE染色观察胸主动脉病理形态变化，ELISA法检测血清中肾素（Renin）、血管紧张素Ⅱ（angiotensin Ⅱ, AngⅡ）、醛固酮（aldosterone, Ald）的含量，免疫组化检测胸主动脉内皮素1（endothelin-1, ET-1）的含量。结果 整理各网络药理学分析平台数据得到祛瘀平肝化痰汤治疗高血压病相关的靶点有162个，最终通过筛选得到EDN1、NOS3、INS、TNF、VEGFA、ACE等34个关键蛋白靶点，主要富集在血管收缩调节、血压调节等生物过程及钙、肾素-血管紧张素系统、肾素分泌等信号通路。动物实验结果显示，中药组和西药组大鼠胸主动脉内膜结构较模型组完善；空白组、中药组、西药组经灌胃4周后，Renin、Ang Ⅱ、Ald表达均较模型组降低（P<0.01）；镜下观察免疫组化结果，模型组的ET-1表达显著高于空白组及各给药组（P<0.05）。结论 祛瘀平肝化痰汤可以通过多途径、多靶点调节血压，其药理作用可能通过干预肾素-血管紧张素-醛固酮系统（renin angiotensin aldosterone system, RAAS）、血管内皮舒缩等得以实现。实验结果表明祛瘀平肝化痰汤能够改善血管状态，降低血清中Renin、Ang Ⅱ、Ald的表达，干预RAAS，抑制血管内ET-1的释放，保护血管内皮。 |
| 关键词: 祛瘀平肝化痰汤 网络药理学 肾素-血管紧张素-醛固酮系统 血管内皮损伤 内皮素-1 |
| DOI：10.3969/j.issn.1674-070X.2022.03.012 |
| Received:September 25, 2021 |
| 基金项目:国家自然科学基金项目（81573941）；胡国恒名医传承工作室（湘中医药函[2018]37号）；湖南省研究生创新项目（CX2018B491）；湖南中医药大学中医学国内一流建设学科。 |
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| Discussion on antihypertensive mechanism and experimental verification of Quyu Pinggan Huatan Decoction based on network pharmacology |
| TIAN Fengming,SHE Ruining,LIN Xiaoyuan,HU Guoheng |
| (Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To explore the possible targets and mechanism of Quyu Pinggan Huatan Decoction in the treatment of hypertension by using network pharmacology, and select some key targets and pathways for experimental verification, so as to provide theoretical support for its clinical application and follow-up research. Methods TCMSP, BATMAN, TCMIP network pharmacological analysis platforms were used to mine the effective components of Quyu Pinggan Huatan Decoction, and SWISS and STITCH databases were used to sort out its action targets; OMIM, TTD and GeneCards databases were used to mine the related targets of hypertension and the intersection with the drug component targets were obtained, and then the component-disease target of Quyu Pinggan Huatan Decoction was obtained; the network diagram of protein-protein interaction was constructed by STRING database and Cytoscape software, and the key targets were screened; finally, the obtained targets and pathways were enriched and analyzed. According to the results of network pharmacology, four groups of SD rats were set up for experimental verification, including blank group, model group, traditional Chinese medicine group and western medicine group. Except the blank group, the other groups were modeled by intraperitoneal injection of N'-nitro-L-arginine (L-NNA). The blank group and model group were given purified water by gavage, the traditional Chinese medicine group was given 20.29 g/kg Quyu Pinggan Huatan Decoction, and the western medicine group was given 2.11 mg/kg captopril suspension by gavage, twice a day for 4 weeks. The pathological changes of thoracic aorta were observed by HE staining, the content of Renin, angiotensin Ⅱ (Ang Ⅱ) and aldosterone (Ald) in serum were detected by ELISA, and the content of endothelin-1 (ET-1) in thoracic aorta was detected by immunohistochemistry. Results After sorting out the data of various network pharmacological analysis platforms, it was found that there were 162 targets related to the treatment of hypertension by Quyu Pinggan Huatan Decoction. Finally, 34 key protein targets such as EDN1, NOS3, INS, TNF, VEGFA and ACE were obtained through screening, which were mainly concentrated in biological processes such as vasoconstriction regulation and blood pressure regulation, calcium signal pathway, renin angiotensin system, renin secretion and other signaling pathways. The results of animal experiments showed that the intimal structure of thoracic aorta in traditional Chinese medicine group and western medicine group was better than that in model group; the expression levels of Renin, Ang Ⅱ and Ald in blank group, traditional Chinese medicine group and western medicine group were lower than those in model group (P<0.01); immunohistochemical results were observed under microscope that, the expression of ET-1 in the model group was significantly higher than that in the blank group and each administration group (P<0.05). Conclusion Quyu Pinggan Huatan Decoction can regulate blood pressure through multiple channels and targets, and its pharmacological effect may be realized by intervening renin angiotensin aldosterone system (RAAS), vascular endothelial relaxation and contraction, etc. The experimental results show that Quyu Pinggan Huatan Decoction can improve the vascular state, reduce the expression of Renin, Ang Ⅱ and Ald in serum, intervene RAAS, inhibit the release of ET-1 in blood vessels and protect vascular endothelium. |
| Key words: Quyu Pinggan Huatan Decoction network pharmacology renin-angiotensin-aldosterone system vascular endothelial injury endothelin-1 |
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