Published Online
on September 27, 2004

A more recent version of this article appeared on October 5, 2004

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Submitted on May 23, 2004
Revised on July 10, 2004
Accepted on July 21, 2004

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, and 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.*Drs Huo and Zhao contributed equally to this work.

^* To whom correspondence should be addressed. E-mail: Yuqing{at}umn.edu.

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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