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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1439.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Lentiviral Transduction of ApoAI Into Hematopoietic Progenitor Cells and Macrophages

Applications to Cell Therapy of Atherosclerosis

Yan Ru Su; John L. Blakemore; Youmin Zhang; MacRae F. Linton; Sergio Fazio

From the Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit (Y.R.S., J.L.B., Y.Z., M.F.L., S.F.), the Department of Pharmacology (M.F.L.), and the Department of Pathology (S.F.), Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Yan Ru Su, or MacRae F. Linton, or Sergio Fazio Vanderbilt University Medical Center, Division of Cardiovascular Medicine, 383 PRB, 2220 Pierce Avenue, Nashville TN 37232-6300. E-mail yan.ru.su{at}vanderbilt.edu, or macrae.linton@vanderbilt.edu, or sergio.fazio@vanerbuilt.edu

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.

Lentivirus-mediated transduction of apoAI increased cholesterol efflux and upregulated ABCA1 and ABCG1 in wild-type and apoE^–/– macrophages. Transplantation of apoAI-expressing HPCs into apoE^–/– mice reduced foam cell formation. Thus, arterial expression of apoAI in macrophages can be a useful tool for cell therapy of atherosclerosis.

Key Words: macrophages • hematopoietic progenitor cells • lentiviral vector • apolipoprotein AI • cholesterol efflux • cell therapy of atherosclerosis