Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters.
The antiatherogenic effect of high-density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) has been largely attributed to their key roles in reverse cholesterol transport (RCT) and cellular cholesterol efflux. Substantial evidence shows that overexpression of human apoA-I reduces atherosclerosis in animal models. However, it is uncertain whether this protection is due to an increase in plasma HDL level or to a local effect in the artery wall. To test the hypothesis that expression of human apoA-I in macrophages can promote RCT in the artery wall, we used a retroviral construct expressing human apoA-I cDNA (MFG-HAI) to transduce ApoE(-/-) bone marrow cells and then transplanted these cells into ApoE(-/-) mice with preexisting atherosclerosis. ApoE(-/-) mice reconstituted with MFG-HAI marrow had a significant reduction (30%) in atherosclerotic lesions in the proximal aorta compared to control mice that received marrow expressing MFG parental virus. Peritoneal macrophages isolated from MFG-HAI mice showed a four- to fivefold increase in mRNA expression levels of both ATP-binding cassette (ABC) A1 and ABCG1 compared to controls. Our data demonstrate that gene transfer-mediated expression of human apoA-I in macrophages can compensate in part for apoE deficiency and delay the progression of atherosclerotic lesions by stimulating ABC-dependent cholesterol efflux and RCT.
Su
Yan Ru
YR
Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6300, USA. yan.ru.su@vanderbilt.edu
Ishiguro
Hiroyuki
H
Major
Amy S
AS
Dove
Dwayne E
DE
Zhang
Wenwu
W
Hasty
Alyssa H
AH
Babaev
Vladimir R
VR
Linton
MacRae F
MF
Fazio
Sergio
S
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000517:prevention & control*; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D015316:Genetic Therapy; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D014161:Transduction, Genetic; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E