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Characterization of atherosclerotic lesions in apo E3-leiden transgenic mice

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Author: Leppänen, P. · Luoma, J.S. · Hofker, M.H. · Havekes, L.M. · Ylä-Herttuala, S.
Type:article
Date:1998
Institution: Gaubius Instituut TNO
Source:Atherosclerosis, 1, 136, 147-152
Identifier: 234315
doi: DOI:10.1016/S0021-9150(97)00196-2
Keywords: Health · Apo E · Familial dyslipoproteinemia · LRP · Oxidized LDL · Scavenger receptor · Animals · Aorta · Apolipoprotein E3 · Apolipoproteins E · Arteriosclerosis · Cholesterol · Electrophoresis, Agar Gel · Foam Cells · Humans · LDL-Receptor Related Protein 1 · Lipoproteins, LDL · Mice · Mice, Inbred C57BL · Mice, Transgenic · Receptors, Immunologic · Receptors, LDL

Abstract

Apo E3-leiden transgenic mice express human dysfunctional apo E variant and develop hyperlipidemia and atherosclerosis on a high fat/high cholesterol diet. We characterized diet-induced atherosclerotic lesions in apo E3-leiden transgenic mice using immunocytochemical methods in order to examine foam cell formation and determine whether advanced atherosclerotic lesions develop in these animals. Special attention was given to the presence of oxidized lipoproteins and expression of lipoprotein receptors. Plasma cholesterol levels in apo E3-leiden mice on an atherogenic diet increased from 2 to 36 mmol/l in 4 months. At this time apo E3-leiden mice had developed lesions, which ranged from early fatty streaks in thoracic and abdominal aorta to advanced lesions in aortic arch. Early fatty streaks were entirely composed of macrophages which also expressed scavenger receptors. Epitopes characteristic of oxidized LDL were present in macrophage-rich foam cells. Advanced atherosclerotic lesions also developed in apo E3-leiden mice including smooth muscle cell cap formation and erosion of the media. Macrophages and epitopes characteristic of oxidized LDL were present in core and shoulder regions. Scavenger receptors were expressed in macrophages in advanced lesions, whereas LDL-receptor-related protein (LRP) was mainly expressed in smooth muscle cells. It is concluded that: (1) macrophages are the major cell type in both early and advanced atherosclerotic lesions; (2) scavenger receptors and oxidized lipoproteins are present in lesion macrophages; and (3) LRP is mostly expressed in smooth muscle cells. Thus, lesions in apo E3-leiden transgenic mice have features in common with human atherosclerosis. Since lesion macrophages also retain their ability to synthesize endogenous apo E, apo E3-leiden transgenic mouse may be a useful model for studies on the development and genetics of atherosclerosis.