Title
Macrophage specific overexpression of the human macrophage scavenger receptor in transgenic mice, using a 180-kb yeast artificial chromosome, leads to enhanced foam cell formation of isolated peritoneal macrophages
Author
de Winther, M.P.J.
van Dijk, K.W.
van Vlijmen, B.J.M.
Gijbels, M.J.J.
Heus, J.J.
Wijers, E.R.
van den Bos, A.C.
Breuer, M.
Frants, R.R.
Havekes, L.M.
Hofker, M.H.
Gaubius instituut TNO
Publication year
1999
Abstract
Macrophage scavenger receptors class A (MSR) are thought to play an important role in atherogenesis by mediating the unrestricted uptake of modified lipoproteins by macrophages in the vessel wall leading to foam cell formation. To investigate the in vivo role of the MSR in this process, a transgenic mouse model expressing both isoforms of the human MSR was generated. A 180-kb yeast artificial chromosome (YAC) containing the human MSR gene (MSR1) with 60- and 40-kb flanking sequence at the 5' and 3' end, respectively, was obtained by reducing the size of a 1050-kb YAC by homologous recombination. This 180-kb YAC was microinjected into mouse oocytes. In the resulting transgenic mice, high levels of mRNA for both type I and type II human MSR1 were detected in peritoneal macrophages and trace levels in other organs, known to contain macrophage-derived cells. Using an antibody against the human MSR, the Kupffer cells in the liver were shown to contain the MSR protein. In vivo clearance of acetyl-LDL was not changed in the MSR1-transgenic mice. However, in vitro studies using peritoneal macrophages from the transgenic mice showed a two-fold increased degradation of acetyl-LDL and cholesterolester accumulation concomitant with a four-fold increase in foam cell formation, as compared to wild-type macrophages. Thus, macrophage specific overexpression of the MSR may lead to increased foam cell formation, which is one of the initial and crucial steps in atherogenesis. Copyright (C) 1999 Elsevier Science Ireland Ltd.
Subject
Biology
Acetyl-low density lipoprotein
Macrophage scavenger receptor
Transgenics
Yeast artificial chromosome
acetyl low density lipoprotein
cholesterol ester
scavenger receptor
animal cell
animal experiment
article
atherogenesis
cell proliferation
controlled study
foam cell
gene overexpression
immunohistochemistry
mouse
nonhuman
peritoneum macrophage
priority journal
transgenic mouse
yeast artificial chromosome
Animals
Base Sequence
Cells, Cultured
Chromosomes, Artificial, Yeast
Disease Models, Animal
Foam Cells
Gene Expression
Humans
Kupffer Cells
Lipoproteins, LDL
Macrophages, Peritoneal
Mice
Mice, Transgenic
Molecular Sequence Data
Polymerase Chain Reaction
Receptors, Immunologic
Receptors, Scavenger
RNA, Messenger
Scavenger Receptors, Class A
Sensitivity and Specificity
Species Specificity
Tissue Distribution
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http://resolver.tudelft.nl/uuid:8cb48ddb-661f-4b13-b076-76ee14bc70ec
DOI
https://doi.org/10.1016/s0021-9150(99)00204-x
TNO identifier
235153
ISSN
0021-9150
Source
Atherosclerosis, 147 (2), 339-347
Document type
article