Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-beta

摘要

Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE~(-/-) mice after high-fat diet treatment. Mindin~(-/-) ApoE~(-/-) mice and macrophage-specific mindin overexpression in ApoE~(-/-) mice (Lyz2-mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin~(-/-) ApoE~(-/-) mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-beta expression via a direct interaction. Importantly, LXR-beta inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-beta.