Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis.

Su YR, Blakemore JL, Zhang Y, Linton MF, Fazio S
Arterioscler Thromb Vasc Biol. 2008 28 (8): 1439-46

PMID: 18497309 · PMCID: PMC2744493 · DOI:10.1161/ATVBAHA.107.160093

OBJECTIVE - We used genetically engineered mouse hematopoietic progenitor cells (HPCs) to investigate the therapeutic effects of human apoAI on atherosclerosis in apoE(-/-) mice.

METHODS AND RESULTS - Lentiviral constructs expressing either human apoAI (LV-apoAI) or green fluorescent protein (LV-GFP) cDNA under a macrophage specific promoter (CD68) were generated and used for ex vivo transduction of mouse HPCs and macrophages. The transduction efficiency was >25% for HPCs and >70% for macrophages. ApoAI was found in the macrophage culture media, mostly associated with the HDL fraction. Interestingly, a significant increase in mRNA and protein levels for ATP binding cassette A1 (ABCA1) and ABCG1 were found in apoAI-expressing macrophages after acLDL loading. Expression of apoAI significantly increased cholesterol efflux in wild-type and apoE(-/-) macrophages. HPCs transduced with LV-apoAI ex vivo and then transplanted into apoE(-/-) mice caused a 50% reduction in atherosclerotic lesion area compared to GFP controls, without influencing plasma HDL-C levels.

CONCLUSIONS - Lentiviral transduction of apoAI into HPCs reduces atherosclerosis in apoE(-/-) mice. Expression of apoAI in macrophages improves cholesterol trafficking in wild-type apoE-producing macrophages and causes upregulation of ABCA1 and ABCG1. These novel observations set the stage for a cell therapy approach to atherosclerosis regression, exploiting the cooperation between apoE and apoAI to maximize cholesterol exit from the plaque.

MeSH Terms (13)

Animals Aorta Apolipoprotein A-I Atherosclerosis Disease Models, Animal Female Genetic Therapy Hematopoietic Stem Cell Transplantation Lentivirus Macrophages Male Rats Transduction, Genetic

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