Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice

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(2alpha)-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.