College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, Liaoning, China.
Department of Cardiology, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Cardiovascular Research Institute, General Hospital of Northern Theater Command, Shenyang, China.
Medicine (Baltimore). 2024 Oct 18;103(42):e40118. doi: 10.1097/MD.0000000000040118.
The Guanxin Shutong capsule (GXST), a traditional Chinese medicine, is commonly used for treating cardiovascular disease, it has shown efficacy in improving symptoms and enhancing the quality of life for patients with heart failure (HF). However, the specific mechanism of action of GXST in HF remains unclear. In this study, we employed a comprehensive approach combining network pharmacology, molecular dynamics (MD) simulations, and in vitro validations to investigate the potential targets and molecular mechanisms of GXST against HF. We collected active ingredients and target genes of GXST, as well as related genes of HF, from multiple public databases. Using bioinformatics analysis, we constructed networks of ingredients-disease-targets and performed functional annotations of the core targets. MD simulations were conducted to verify the binding between the core protein-ligand complexes. In vitro evaluations, including cell proliferation, apoptosis, and protein expression in human umbilical vein endothelial cells (HUVECs) and H9C2 cells were treated with GXST, were performed for pharmacodynamics evaluation. Network analysis revealed 320 intersection genes and 74 active ingredients in the Herbs-ingredients-target genes-disease network. We identified key active ingredients and target genes that overlapped. The KEGG pathways of the intersection genes were primarily enriched in the PI3K-Akt signaling pathway and apoptosis. The protein-protein interaction network highlighted proteins such as AKT1, VEGFR2, and eNOS. MD simulations confirmed stable docking and lower binding energy between 4 identified ingredients (kaempferol, quercetin, (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl) chroman-4-one, and ellagic acid) and their respective core proteins (VEGFR2, eNOS, and AKT). In vitro experiments demonstrated the protective effects of GXST against H2O2-induced apoptosis in both HUVECs and H9C2 cells. Notably, consistent with the in silico predictions, GXST effectively activates the VEGFR2/AKT/eNOS signaling pathways in HUVECs. This study provides insights into the underlying mechanism of GXST's therapeutic effects in heart failure. The involvement of the VEGFR2/AKT/eNOS signaling pathways suggests their importance in further elucidating and applying GXST in the clinical treatment of heart failure.
冠心舒通胶囊（GXST）是一种中药，常用于治疗心血管疾病，已显示出改善心力衰竭（HF）患者症状和提高生活质量的功效。然而，GXST 治疗 HF 的具体作用机制尚不清楚。在这项研究中，我们采用网络药理学、分子动力学（MD）模拟和体外验证相结合的综合方法，研究 GXST 治疗 HF 的潜在靶点和分子机制。我们从多个公共数据库中收集 GXST 的活性成分和靶基因，以及 HF 的相关基因。通过生物信息学分析，我们构建了成分-疾病-靶标网络，并对核心靶标进行了功能注释。进行 MD 模拟以验证核心蛋白-配体复合物的结合。在体外评估中，包括 GXST 处理的人脐静脉内皮细胞（HUVEC）和 H9C2 细胞的增殖、凋亡和蛋白表达，进行药效学评价。网络分析显示， Herbs-ingredients-target genes-disease 网络中有 320 个交集基因和 74 种活性成分。我们鉴定出关键的活性成分和重叠的靶基因。交集基因的 KEGG 途径主要富集在 PI3K-Akt 信号通路和细胞凋亡中。蛋白质-蛋白质相互作用网络突出了 AKT1、VEGFR2 和 eNOS 等蛋白质。MD 模拟证实了 4 种鉴定出的成分（山奈酚、槲皮素、（2R）-5,7-二羟基-2-（4-羟基苯基）色满-4-酮和鞣花酸）及其各自核心蛋白（VEGFR2、eNOS 和 AKT）之间稳定的对接和较低的结合能。体外实验表明，GXST 对 HUVEC 和 H9C2 细胞中 H2O2 诱导的凋亡具有保护作用。值得注意的是，与计算机模拟结果一致，GXST 可有效激活 HUVEC 中的 VEGFR2/AKT/eNOS 信号通路。本研究为 GXST 治疗心力衰竭的潜在机制提供了见解。VEGFR2/AKT/eNOS 信号通路的参与表明，该通路对于进一步阐明和应用 GXST 治疗心力衰竭具有重要意义。
