Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China.
The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
Comb Chem High Throughput Screen. 2024;27(18):2776-2789. doi: 10.2174/0113862073267432230925112002.
Pulmonary Arterial Hypertension (PAH) is a fatal disease with high morbidity and mortality. Cordycepin has anti-inflammatory, antioxidant and immune enhancing effects. However, the role of Cordycepin in the treatment of PAH and its mechanism is not clear.
The Cordycepin structure and PAH-related gene targets were obtained from public databases. The KEGG and GO enrichment analysis of common targets was performed in DAVID. PPI networks were also mapped using the STRING platform. AutoDock Vina, AutoDockTools, ChemBio3D and Pymol tools were selected for molecular docking of key targets. The therapeutic effects of Cordycepin on PAH were observed in Monocrotaline (MCT)-induced PAH rats and platelet-derived growth factor BB (PDGFBB)-induced rat pulmonary artery smooth muscle cells (PASMCs). The right ventricular systolic pressure (RVSP) was detected. HE staining, Western Blot, Scratch assay, EDU and TUNEL assays were used, respectively.
Through Network Pharmacology and molecular docking, the Cordycepin-PAH core genes were found to be TP53, AKT1, CASP3, BAX and BCL2L1. In MCT-induced PAH rats, the administration of Cordycepin significantly reduced RVSP, and inhibited pulmonary vascular remodeling. In PDGFBB-induced PASMCs, Cordycepin reduced the migration and proliferation of PASMCs and promoted apoptosis. After the Cordycepin treatment, the protein expressions of TP53, Cleaved CASP3 and BAX were significantly increased, while the protein expressions of p-AKT1 and BCL2L1 were significantly decreased in MCT-PAH rats and PDGFBB-induced PASMCs.
This study identified that TP53, AKT1, CASP3, BAX, and BCL2L1 were the potential targets of Cordycepin against PAH by ameliorating pulmonary vascular remodeling, inhibiting the abnormal proliferation and migration of PASMCs and increasing apoptosis of PASMCs. which provided a new understanding of the pharmacological mechanisms of Cordycepin in the treatment of PAH.
肺动脉高压（PAH）是一种高发病率和死亡率的致命疾病。蛹虫草素有抗炎、抗氧化和增强免疫的作用。然而，蛹虫草素在 PAH 治疗中的作用及其机制尚不清楚。
从公共数据库中获取蛹虫草素的结构和与 PAH 相关的基因靶点。在 DAVID 中对共同靶点进行 KEGG 和 GO 富集分析。使用 STRING 平台绘制 PPI 网络。选择 AutoDock Vina、AutoDockTools、ChemBio3D 和 Pymol 工具对关键靶点进行分子对接。在野百合碱（MCT）诱导的 PAH 大鼠和血小板衍生生长因子 BB（PDGFBB）诱导的大鼠肺动脉平滑肌细胞（PASMCs）中观察蛹虫草素对 PAH 的治疗作用。检测右心室收缩压（RVSP）。分别进行 HE 染色、Western blot、划痕实验、EDU 和 TUNEL 实验。
通过网络药理学和分子对接，发现蛹虫草素-PAH 核心基因有 TP53、AKT1、CASP3、BAX 和 BCL2L1。在 MCT 诱导的 PAH 大鼠中，蛹虫草素给药可显著降低 RVSP，并抑制肺血管重构。在 PDGFBB 诱导的 PASMCs 中，蛹虫草素可减少 PASMC 的迁移和增殖，并促进凋亡。蛹虫草素处理后，MCT-PAH 大鼠和 PDGFBB 诱导的 PASMCs 中 TP53、Cleaved CASP3 和 BAX 的蛋白表达明显增加，而 p-AKT1 和 BCL2L1 的蛋白表达明显降低。
本研究通过改善肺血管重构、抑制 PASMC 异常增殖和迁移以及增加 PASMC 凋亡，鉴定出蛹虫草素可能通过以下机制治疗 PAH：TP53、AKT1、CASP3、BAX 和 BCL2L1。这为蛹虫草素治疗 PAH 的药理机制提供了新的认识。
