Article

Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse.

Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Circulation Research (impact factor: 9.49). 04/2007; 100(5):670-7. DOI:10.1161/01.RES.0000260204.40510.aa pp.670-7
Source: PubMed

ABSTRACT 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 (125)I-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-alpha, 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.

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Keywords

blocking lipoprotein internalization
 
foam cell formation
 
higher frequency
 
hypercholesterolemic mice
 
inflammatory responses
 
lack macrophage LRP
 
lethally irradiated female LDLR(-/-)
 
LRP increases atherogenesis
 
Macrophage low-density lipoprotein receptor-related protein
 
macrophage LRP
 
macrophage LRP increases matrix metalloproteinase-9
 
macrophage LRP modulates atherogenesis
 
macrophage LRP(-/-)
 
matrix metalloproteinase-9
 
monocyte chemoattractant protein type-1
 
proximal aorta macrophage cellularity
 
serum lipoprotein levels
 
transgenic mice
 
tumor necrosis factor-alpha
 
wild-type cells