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(Circulation Research. 2007;100:670.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Deletion of Macrophage LDL Receptor–Related Protein Increases Atherogenesis in the Mouse

Cheryl D. Overton, Patricia G. Yancey, Amy S. Major, MacRae F. Linton, Sergio Fazio

From the Atherosclerosis Research Unit (C.D.O., P.G.Y., A.S.M., M.F.L., S.F.), Division of Cardiology, Department of Medicine; and Departments of Pathology (C.D.O., S.F.) and Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Sergio Fazio, 2220 Pierce Ave, 383 PRB, Vanderbilt University, Nashville, TN 37232. E-mail sergio.fazio{at}vanderbilt.edu

Macrophage low-density lipoprotein receptor–related protein (LRP) mediates internalization of remnant lipoproteins, and it is generally thought that blocking lipoprotein internalization will reduce foam cell formation and atherogenesis. Therefore, our study examined the function of macrophage LRP in atherogenesis. We generated transgenic mice that specifically lack macrophage LRP through Cre/lox recombination. Transplantation of macrophage LRP^–/– bone marrow into lethally irradiated female LDLR^–/– recipient mice resulted in a 40% increase in atherosclerosis. The difference in atherosclerosis was not caused by altered serum lipoprotein levels. Furthermore, deletion of macrophage LRP decreased uptake of ¹²⁵I–very-low-density lipoprotein compared with wild-type cells in vitro. The increase in atherosclerosis was accompanied by increases in monocyte chemoattractant protein type-1, tumor necrosis factor-, and proximal aorta macrophage cellularity. We also found that deletion of macrophage LRP increases matrix metalloproteinase-9. This increase in matrix metalloproteinase-9 was associated with a higher frequency of breaks in the elastic lamina. Contrary to what was found with other lipoprotein receptors, deletion of LRP increases atherogenesis in hypercholesterolemic mice. Our data support the hypothesis that macrophage LRP modulates atherogenesis through regulation of inflammatory responses.

Key Words: low-density lipoprotein receptor–related protein • atherosclerosis • lipoproteins • metalloproteinase • macrophage

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