Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E–Deficient Mice

Abstract

Background— Mice lacking leukocyte type 12/15-lipoxygenase (12/15-LO) show reduced atherosclerosis in several models. 12/15-LO is expressed in a variety of cells, including vascular cells, adipocytes, macrophages, and cardiomyocytes. The purpose of this study was to determine which cellular source of 12/15-LO is important for atherosclerosis. Methods and Results— Bone marrow from 12/15-LO −/− /apoE −/− mice was transplanted into apoE −/− mice and vice versa. Deficiency of 12/15-LO in bone marrow cells protected apoE −/− mice fed a Western diet from atherosclerosis to the same extent as complete absence of 12/15-LO, although plasma 8,12- iso -iPF 2α -IV, a measure of lipid peroxidation, remained elevated. 12/15-LO −/− /apoE −/− mice regained the severity of atherosclerotic lesion typical of apoE −/− mice after replacement of their bone marrow cells with bone marrow from apoE −/− mice. Peritoneal macrophages obtained from wild-type but not 12/15-LO −/− mice caused endothelial activation in the presence of native LDL. Absence of 12/15-LO decreased the ability of macrophages to form foam cells when exposed to LDL. Conclusions— We conclude that macrophage 12/15-LO plays a dominant role in the development of atherosclerosis by promoting endothelial inflammation and foam cell formation.