Abstract
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.
Original language | English (US) |
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Pages (from-to) | 576-583 |
Number of pages | 8 |
Journal | Molecular Therapy |
Volume | 8 |
Issue number | 4 |
DOIs | |
State | Published - Oct 2003 |
Externally published | Yes |
Keywords
- ABCA1
- ABCG1
- Apolipoprotein A-I
- Apolipoprotein E deficiency
- Atherosclerosis
- Bone marrow transplantation
- Cholesterol efflux
- Gene therapy
- Macrophages
- Retrovirus
- Reverse cholesterol transport
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery