Quercetin Induces Macrophage Polarization through PI3K-AKT Pathway in Atherosclerosis: Network Pharmacology, Molecule Docking and in vitro Analysis

Abstract

Background: Quercetin (QU) is a major flavonoid in multiple herbs with wide biological effects, while its role in preventing atherosclerosis progression remains largely unknown. Objectives: In this study, we aimed to uncover the effect and underlying mechanism of QU in treating atherosclerosis. Methods: Network pharmacology and protein-protein interaction analysis were conducted to predict potential targets of QU in treating atherosclerosis. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Cell viability, apoptosis, and cell cycle assays were conducted to evaluate the biological effects of QU on atherosclerosis-associated macrophages. Genome expression sequencing (RNA-seq) was performed to identify differentially expressed genes and regulated pathways after QU treatments. Macrophage differentiation and fluorescence-activated cell sorting (FACS), western blot, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were further performed to verify the results of RNA-seq and the effects of QU on regulating the indicated pathway. Results: In this study, 180 potential targets were identified by network pharmacology analysis, and multiple anti-inflammatory pathways were enriched in QU treating atherosclerosis. Our data also indicated that QU promotes macrophage cell viability by reducing cell apoptosis and cell cycle arrest in an atherosclerosis-associated macrophage cell model. Additionally, RNA-seq revealed that the PI3K-AKT pathway might be the significantly upregulated pathway after QU treatment in macrophages to induce M2 polarization, which was further verified by protein and RNA detection. Conclusions: Taken together, we are the first to combine multiple database analyses and genome expression data to uncover the protective effect of QU in treating atherosclerosis by inducing M2 polarization through regulating the PI3K-AKT pathway.