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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1647.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Conditional Knockout of Macrophage PPARIncreases Atherosclerosis in C57BL/6 and Low-Density Lipoprotein Receptor–Deficient Mice

Vladimir R. Babaev; Patricia G. Yancey; Sergey V. Ryzhov; Valentina Kon; Matthew D. Breyer; Mark A. Magnuson; Sergio Fazio; MacRae F. Linton

From the Departments of Medicine (V.R.B., P.G.Y., S.V.R., S.F., M.F.L.), Pharmacology (M.F.L.), Pathology (S.F.), Nephrology (V.K., M.D.B.), and Molecular Physiology & Biophysics (M.A.M.), Vanderbilt University Medical Center, Nashville, Tenn.

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

Objective— Peroxisome proliferator-activated receptor gamma (PPAR) is highly expressed in macrophage-derived foam cells of atherosclerotic lesions, and its expression may have a dramatic impact on atherosclerosis.

Methods and Results— To investigate the contribution of macrophage PPAR expression on atherogenesis in vivo, we generated macrophage-specific PPAR knockout (MacPPARKO) mice. C57BL/6 and low-density lipoprotein (LDL) receptor–deficient (LDLR^–/–) mice were reconstituted with MacPPARKO or wild-type marrow and challenged with an atherogenic diet. No differences were found in serum lipids between recipients reconstituted with MacPPARKO and wild-type marrow. In contrast, both C57BL/6 and LDLR^–/– mice transplanted with MacPPARKO marrow had significantly larger atherosclerotic lesions than control recipients. In addition, MacPPARKOLDLR^–/– mice had higher numbers of macrophages in atherosclerotic lesions compared with controls. Peritoneal macrophages isolated from the MacPPARKO mice had decreased uptake of oxidized but not acetylated LDL and showed no changes in either cholesterol efflux or inflammatory cytokine expression. Macrophages from MacPPARKO mice had increased levels of migration and CC chemokine receptor 2 (CCR2) expression compared with wild-type macrophages.

Conclusion— Thus, macrophage PPAR deficiency increases atherosclerosis under conditions of mild and severe hypercholesterolemia, indicating an antiatherogenic role for PPAR, which may be caused, at least in part, by modulation of CCR2 expression and monocyte recruitment.

To investigate the contribution of macrophage PPAR on atherogenesis, we generated macrophage-specific PPAR knockout (MacPPARKO) mice. C57BL/6 and low-density lipoprotein (LDL) receptor–deficient mice were reconstituted with MacPPARKO marrow. These mice had significantly larger atherosclerotic lesions than control recipients. MacPPARKO macrophages had decreased uptake of oxidized LDL and increased CCR2 expression levels.

Key Words: ABCA1 • atherosclerosis • CCR2 expression • cholesterol efflux • macrophages • scavenger receptor CD36

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