Depletion of β-arrestin-1 in macrophages enhances atherosclerosis in ApoE−/− mice

Abstract

Autophagy in atherosclerotic plaque macrophage contributes to the alleviation of atherosclerosis through the promotion of lipid metabolism. β-arrestins are multifunctional proteins participating various kinds of cellular signaling pathways. Here we aimed to determine the role of β-arrestin-1, an important member of β-arrestin family, in atherosclerosis, and whether autophagy was involved in this process. ApoE−/−β-arrestin-1fl/flLysM-Cre mice were created through bone marrow transplantation for the atherosclerosis model with conditional myeloid knocking out β-arrestin-1. Bone marrow-derived macrophages (BMDMs) were used for the in vitro studies. Oil red O staining was used to detect the lesional area. F4/80, Masson trichrome and picro-Sirius red staining were applied for the determination of plaque stability. Real-time PCR was used for the detection of levels of lipid metabolism-related receptors. Electron microscopy and tandem fluorescent mRFP-GFP-LC3 plasmid was applied to test autophagy level. We found that β-arrestin-1 was highly increased in expression in plaque macrophage on the occurrence of atherosclerosis. Conditional myeloid knocking out β-arrestin-1 largely promotes plaque formation and vulnerability. In murine macrophage with lipid loading, knocking down β-arrestin-1 enhanced foam cell formation and levels of plasma and cellular cholesterol, while overexpressing β-arrestin-1 led to the opposite effects. The alleviative effects induced by macrophage β-arrestin-1 in atherosclerosis were involved in autophagy, based on the reduction of autophagy level with the knocking down of macrophage β-arrestin-1 and administration of autophagy inhibitors which largely attenuated the decreasing effect on foam cell formation. Our results demonstrated for the first time that macrophage β-arrestin-1 protected against atherosclerosis through the induction of autophagy.