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

Research output: Contribution to journalArticle

88 Citations (Scopus)

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 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-α, 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.

Original languageEnglish (US)
Pages (from-to)670-677
Number of pages8
JournalCirculation Research
Volume100
Issue number5
DOIs
StatePublished - Mar 2007
Externally publishedYes

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Lipoprotein Receptors
Atherosclerosis
Macrophages
Proteins
Lipoproteins
Matrix Metalloproteinase 9
LDL-Receptor Related Proteins
Foam Cells
VLDL Lipoproteins
Chemokine CCL2
LDL Receptors
Transgenic Mice
Genetic Recombination
Aorta
Tumor Necrosis Factor-alpha
Transplantation
Bone Marrow

Keywords

  • Atherosclerosis
  • Lipoproteins
  • Low-density lipoprotein receptor-related protein
  • Macrophage
  • Metalloproteinase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. / Overton, Cheryl D.; Yancey, Patricia G.; Major, Amy S.; Linton, MacRae F.; Fazio, Sergio.

In: Circulation Research, Vol. 100, No. 5, 03.2007, p. 670-677.

Research output: Contribution to journalArticle

Overton, Cheryl D. ; Yancey, Patricia G. ; Major, Amy S. ; Linton, MacRae F. ; Fazio, Sergio. / Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. In: Circulation Research. 2007 ; Vol. 100, No. 5. pp. 670-677.
@article{f1254be2721a4f74b57e3c2b7542623c,
title = "Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse",
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 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-α, 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.",
keywords = "Atherosclerosis, Lipoproteins, Low-density lipoprotein receptor-related protein, Macrophage, Metalloproteinase",
author = "Overton, {Cheryl D.} and Yancey, {Patricia G.} and Major, {Amy S.} and Linton, {MacRae F.} and Sergio Fazio",
year = "2007",
month = "3",
doi = "10.1161/01.RES.0000260204.40510.aa",
language = "English (US)",
volume = "100",
pages = "670--677",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse

AU - Overton, Cheryl D.

AU - Yancey, Patricia G.

AU - Major, Amy S.

AU - Linton, MacRae F.

AU - Fazio, Sergio

PY - 2007/3

Y1 - 2007/3

N2 - 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 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-α, 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.

AB - 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 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-α, 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.

KW - Atherosclerosis

KW - Lipoproteins

KW - Low-density lipoprotein receptor-related protein

KW - Macrophage

KW - Metalloproteinase

UR - http://www.scopus.com/inward/record.url?scp=33947715605&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33947715605&partnerID=8YFLogxK

U2 - 10.1161/01.RES.0000260204.40510.aa

DO - 10.1161/01.RES.0000260204.40510.aa

M3 - Article

VL - 100

SP - 670

EP - 677

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 5

ER -