Myo1f regulates monocyte adhesion and contributes to atherosclerosis via MRTFA-dependent ITGB2 expression

Abstract

Background

Monocyte adhesion to vascular endothelial cells is a critical step in the pathogenesis of atherosclerosis. While unconventional myosins are known to participate in various cellular activities, their specific role in monocyte-endothelium adhesion remains unclear.In the present study, we investigated the effects of Myosin IF (Myo1f), a class I unconventional myosin, on atherosclerosis and its underlying mechanisms.

Methods

A high-cholesterol diet was administered to apolipoprotein E-KO (Apoe^−/−) mice to establish an atherosclerosis model, which was further combined with Myo1f knockout to investigate the specific role of Myo1f in atherosclerosis development. Bone marrow transplantation was conducted to assess the significance of Myo1f in myeloid cells related to atherosclerosis. Peripheral blood mononuclear cells (PBMCs) from patients with non-coronary artery disease (non-CAD) and coronary artery disease (CAD) were isolated to examine the correlation between Myo1f and human atherosclerosis. Co-immunoprecipitation mass spectrometry analysis was performed to identify molecules associated with Myo1f, which were subsequently validated and mechanistically investigated through both in vivo and in vitro experiments. Additionally, potential therapeutic drugs for atherosclerosis were explored using the Apoe^−/− mouse model.

Results

Myo1f expression was found to be significantly increased in PBMCs of patients with coronary artery disease. Moreover, Myo1f-deficient mice exhibited a notable reduction in atherosclerotic plaque area and lipid deposition compared to Apoe^−/− mice. Notably, monocyte Myo1f deletion obviously reduced its integrin β2 (ITGB2) expression, consequently impeding the adhesion of monocytes to vascular endothelial cells. Mechanistically, Myo1f promoted actin polymerization by recruiting epithelial protein lost in neoplasm (EPLIN) and depolymerization of G-actin/myocardin-related transcription factor A (MRTFA), leading to the nuclear translocation of MRTFA and upregulation of ITGB2 transcriptional expression. Treatment with CCG-1423, a MRTFA inhibitor, resulted in reduced atherosclerotic lesions in Apoe^−/− mice.

Conclusions

Our data indicate that Myo1f regulates monocyte adhesion and contributes to the pathogenesis of atherosclerosis by recruiting EPLINα, which stabilizes F-actin. This stabilization enhances MRTFA nuclear translocation, thereby promoting ITGB2 transcription.