Retrovirus-mediated expression of apolipoprotein A-I in the macrophage protects against atherosclerosis in vivo.
We have previously reported that the lack of apolipoprotein (apo) E expression by macrophages promotes foam cell formation in vivo. Because transgenic mice overexpressing human apoA-I from the liver (h-apoA-I TgN) are protected from the atherogenesis induced by apoE deficiency, we hypothesized that the presence of apoA-I in the vessel wall could reduce the negative effect of apoE deficiency on lesion growth. To address this issue, we used both retroviral transduction and transgenic approaches to produce in vivo systems where apoA-I is expressed from macrophages. In the retroviral transduction study, apoA-I-deficient (apoA-I(-/-)) mice reconstituted with apoE-deficient (apoE(-/-)) bone marrow cells that were infected with a retroviral vector expressing human apoA-I (MFG-HAI) had 95% lower atherosclerotic lesion area than that of recipients of apoE(-/-) bone marrow cells infected with the parental virus (MFG). To determine whether the protective effect of locally produced apoA-I was due to the lack of systemic apoA-I, we conducted a different experiment using h-apoA-I TgN mice as recipients of apoE(-/-) bone marrow with or without human apoA-I (driven by a macrophage-specific transgene defined as mphi-AI). Aortic lesion area in apoE(-/-)/mphi-AI --> h-apoA-I TgN mice was decreased by 85% compared with apoE(-/-) --> h-apoA-I TgN mice. These data demonstrate that expression of apoA-I from macrophages protects against atherogenesis without affecting plasma apoA-I and high density lipoprotein cholesterol levels.
Ishiguro
H
H
Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6300, USA.
Yoshida
H
H
Major
A S
AS
Zhu
T
T
Babaev
V R
VR
Linton
M F
MF
Fazio
S
S
D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000737:chemistry; D001053:Apolipoproteins / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012190:Retroviridae / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D019076:Transgenes
D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D008075:Lipoproteins, HDL