Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1439-1446 |
Number of pages | 8 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 28 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2008 |
Externally published | Yes |
Keywords
- Apolipoprotein ai
- Cell therapy of atherosclerosis
- Cholesterol efflux
- Hematopoietic progenitor cells
- Lentiviral vector
- Macrophages
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine