IFITM1 promotes proliferation, migration and macrophage-like transdifferentiation of vascular smooth muscle cells via c-Src/MAPK/GATA2/E2F2 pathway in atherosclerosis.

Atherosclerosis (AS) stands as the primary culprit behind the high morbidity and mortality globally. The aberrant proliferation, migration, and transdifferentiation of vascular smooth muscle cells (VSMCs) are recognized as the crucial factors in the development of atherosclerotic plaques. Interferon-induced transmembrane protein 1 (IFITM1) is verified as a cellular regulatory factor for various diseases but its regulatory role in VSMCs remains unclear. Our objective was to assess the impacts of IFITM1 on VSMC proliferation, migration, and transdifferentiation, along with the underlying molecular mechanisms. RNA sequencing analysis was used to pinpoint differentially expressed genes. Plaque samples from AS patients were analyzed to determine the expression of IFITM1. Experiments such as cell viability, flow cytometry, wound healing, transwell and Western blotting assays were carried out to detect the pathways through which IFITM1 affected VSMC proliferation, migration, and transdifferentiation. The function of IFITM1 in the formation of atherosclerotic plaques was assessed by utilizing the ApoE-/- mouse model. The results showed that the IFITM1 expression was significantly increased in plaque samples from AS rats and patients. Overexpression of IFITM1 markedly promoted VSMC proliferation, migration, and macrophage-like transdifferentiation. Mechanistically, overexpression of IFITM1 upregulated the levels of p-tyrosine-protein kinase (p-Src), p-p38 MAP kinases (p-MAPK), p-GATA-binding factor 2 (p-GATA2) and E2F transcription Factor 2 (E2F2). In vivo experiments demonstrated that overexpression of IFITM1 accelerated the formation of atherosclerotic plaques. In conclusion, IFITM1 promotes VSMC proliferation, migration, and macrophage-like transdifferentiation via the c-Src/MAPK/GATA2/E2F2 pathway, suggesting that IFITM1 may be a possible target for treating AS.