Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse.
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.
Overton
Cheryl D
CD
Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Yancey
Patricia G
PG
Major
Amy S
AS
Linton
MacRae F
MF
Fazio
Sergio
S
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
D004041:Dietary Fats; D018836:Inflammation Mediators; D026503:Low Density Lipoprotein Receptor-Related Protein-1