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(Circulation. 2004;110:2024-2031.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

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

Yuqing Huo, MD, PhD^*; Lei Zhao, MD^*; Matthew Craig Hyman, BS; Pavel Shashkin, PhD; Brian L. Harry, BS; Tracy Burcin, MS; S. Bradley Forlow, PhD; Matthew A. Stark, BS; David F. Smith, MS; Sean Clarke, BS; Suseela Srinivasan, PhD; Catherine C. Hedrick, PhD; Domenico Praticò, MD; Joseph L. Witztum, MD; Jerry L. Nadler, MD; Colin D. Funk, PhD; Klaus Ley, MD

From the University of Virginia (Y.H., M.C.H., P.S., B.L.H., T.B., S.B.F., M.A.S., D.F.S., S.C., S.S., C.C.H., J.L.N., K.L.), Charlottesville, Va; University of Pennsylvania (L.Z., D.P., C.D.F.), Philadelphia, Pa; and University of California (J.L.W), San Diego, Calif.

Correspondence to Yuqing Huo, MD, PhD, Cardiovascular Division and Vascular Biology Center, University of Minnesota, MMC 508, 420 Delaware St SE, Minneapolis, MN 55455. E-mail Yuqing{at}umn.edu

Received May 23, 2004; revision received July 10, 2004; accepted July 21, 2004.

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-iPF₂-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.

Key Words: atherosclerosis • cell adhesion molecules • endothelium • lipids

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