Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters

Yan Ru Su, Hiroyuki Ishiguro, Amy S. Major, Dwayne E. Dove, Wenwu Zhang, Alyssa H. Hasty, Vladimir R. Babaev, MacRae F. Linton, Sergio Fazio

    Research output: Contribution to journalArticle

    18 Scopus citations

    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 languageEnglish (US)
    Pages (from-to)576-583
    Number of pages8
    JournalMolecular Therapy
    Volume8
    Issue number4
    DOIs
    StatePublished - Oct 2003

    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

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