Role of dysregulated macrophage subpopulation ratios and functional changes in the development of coronary atherosclerosis

Abstract Coronary heart disease is one of the most significant risk factors affecting human health worldwide. Its pathogenesis is intricate, with atherosclerosis being widely regarded as the leading cause. Aberrant lipid metabolism in macrophages is recognized as one of the triggering factors in atherosclerosis development. To investigate the role of macrophages in the formation of coronary artery atherosclerosis, we utilized single‐cell data from wild‐type mice obtained from the aortic roots and ascending aortas after long‐term high‐fat diet feeding, as deposited in GSE131776. Seurat software was employed to refine the single‐cell data in terms of scale and cell types, facilitating the identification of differentially expressed genes. Through the application of differential expression genes, we conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses at 0, 8 and 16 weeks, aiming to uncover pathways with the most pronounced functional alterations as the high‐fat diet progressed. The AddModuleScore function was employed to score the expression of these pathways across different cell types. Subsequently, macrophages were isolated and further subdivided into subtypes, followed by an investigation into intercellular communication within these subtypes. Subsequent to this, we induced THP‐1 cells to generate foam cells, validating critical genes identified in prior studies. The results revealed that macrophages underwent the most substantial functional changes as the high‐fat diet progressed. Furthermore, two clusters were identified as potentially playing pivotal roles in macrophage functional regulation during high‐fat diet progression. Additionally, macrophage subtypes displayed intricate functionalities, with mutual functional counterbalances observed among these subtypes. The proportions of macrophage subtypes and the modulation of anti‐inflammatory and pro‐inflammatory functions played significant roles in the development of coronary artery atherosclerosis.