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(Circulation. 2007;116:1404-1412.)
© 2007 American Heart Association, Inc.

Vascular Medicine

Macrophage Expression of Peroxisome Proliferator–Activated Receptor- Reduces Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

Vladimir R. Babaev, PhD; Hiroyuki Ishiguro, MD; Lei Ding, BA; Patricia G. Yancey, PhD; Dwayne E. Dove, MD, PhD; William J. Kovacs, MD; Clay F. Semenkovich, MD; Sergio Fazio, MD, PhD; MacRae F. Linton, MD

From the Department of Medicine (V.R.B., H.I., L.D., P.G.Y., D.E.D., S.F., M.F.L.), Pathology (S.F.), and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, Tenn; Division of Endocrinology and Metabolism (W.J.K.), University of Texas, Dallas, Tex; and Washington University (C.F.S.), St. Louis, Mo.

Correspondence to Vladimir Babaev, Sergio Fazio, or MacRae F. Linton, Department of Cardiovascular Medicine, Vanderbilt University School of Medicine, 312 PRB, Nashville, TN 37232-6300. E-mail vladimir.babaev{at}vanderbilt.edu, sergio.fazio@vanderbilt.edu, or macrae.linton@vanderbilt.edu

Received December 15, 2006; accepted July 12, 2007.

Background— The peroxisome proliferator–activated receptor- (PPAR) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPAR ligands have been shown to reduce cardiovascular events in high-risk subjects. PPAR expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes.

Methods and Results— To examine the contribution of PPAR expression by bone marrow–derived cells in atherosclerosis, male and female low-density lipoprotein receptor–deficient (LDLR^–/–) mice were reconstituted with bone marrow from PPAR^–/– or PPAR^+/+ mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPAR^–/–LDLR^–/– mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPAR^–/–LDLR^–/– mice also had larger (44%) atherosclerotic lesions in the proximal aorta than male PPAR^+/+LDLR^–/– mice. Peritoneal macrophages from PPAR^–/– mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPAR^–/– macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-B–regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-B gene expression levels in vivo in atherosclerotic lesions of PPAR^–/–LDLR^–/– mice compared with the lesions of control PPAR^+/+LDLR^–/– mice.

Conclusions— These data demonstrate that PPAR expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.

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