Potential mechanisms of Qili Qiangxin capsule to prevent pulmonary arterial hypertension based on network pharmacology analysis in a rat model

BACKGROUND: Qili Qiangxin capsule (QQC), a traditional Chinese medicine, has recently been approved to treat pulmonary arterial hypertension (PAH). However, the multi-target mechanism through which QQC acts on PAH has not been clarified. The objective of this study was to explore the pharmacological processes of QQC for treating PAH. METHODS: The rat model of PAH was established by administering monocrotaline (MCT). The impact of QQC on PAH was studied in treatment group that received QQC orally over a period of 4 weeks. The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was searched for active compounds and QQC targets that were then identified and downloaded. Then, PAH-related targets were obtained from five databases [GeneCards, DrugBank, Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), and PharmGKB]. The QQC targets for PAH were compiled after they had been overlapped with one another. Furthermore, the STRING network platform, the Cytoscape tool, networks of protein-protein interaction (PPI) were used, and core target analyses were carried out. Moreover, molecular docking techniques were employed in this research. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment studies of overlapping targets were carried out using the R software (version: 4.0.5; Lucent Technologies Co., Ltd., China). Finally, we verified the synergistic action mechanisms using western blotting and immunofluorescence analysis on PAH rats who were treated with or without QQC. RESULTS: The search of the TCMSP database showed that there were 11 active ingredients in QQC that treated PAH. PPI network showed that AKT1, TP53, JUN, and MAPK1 were the most important targets in the treatment of PAH. Moreover, Molecular docking techniques showed that the affinity between the bioactive compounds in QQC and their PAH targets was strong. In vivo experiments demonstrated that QQC may attenuate the progression of MCT-stimulated PAH in rats. Furthermore, the protective effect was mediated by inhibiting the PI3K/AKT pathway. The active compounds mainly included quercetin, kaempferol, formononetin, and luteolin, which had good docking scores and targeted the AKT protein. CONCLUSIONS: QQC might activate the PI3K/AKT signaling pathway to ameliorate MCT-induced PAH. These findings support the clinical use of QQC and provide the foundation for further studies.