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(Circulation. 2001;104:2820.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Isoform-Specific Effects of Apolipoprotein E on Atherogenesis

Gene Transduction Studies in Mice

Hiroaki Yoshida, MD; Alyssa H. Hasty, PhD; Amy S. Major, PhD; Hiroyuki Ishiguro, MD; Yan Ru Su, MD; Linda A. Gleaves; Vladimir R. Babaev, PhD; MacRae F. Linton, MD; Sergio Fazio, MD, PhD

From the Departments of Medicine (all authors), Pediatrics (H.Y.), Pathology (S.F.), and Pharmacology (M.F.L.), Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Dr Alyssa H. Hasty, Dr Sergio Fazio, or Dr MacRae F. Linton, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 383 Preston Research Bldg, Nashville, TN 37232-6300. E-mail alyssa.hasty{at}mcmail.vanderbilt.edu, sergio.fazio@mcmail.vanderbilt.edu, or macrae.linton@mcmail.vanderbilt.edu

Background— We recently used a bone marrow–based gene therapy approach to show that small amounts of retrovirus-derived human apolipoprotein E3 (apoE3) produced by macrophages are protective against early atherosclerosis in apoE-deficient mice.

Methods and Results— In the present study, we evaluated whether the effect produced by macrophage-derived apoE3 is related to its ability to bind cellular membranes. To this end, we used apoE2 and apoEcys142, dysfunctional human variants with reduced binding to the LDL receptor or to heparan sulfate proteoglycans, respectively. ApoE-deficient mice, 5 weeks of age, received transplants of apoE^-/- bone marrow cells transduced with either parental retrovirus or apoE3, apoE2, or apoEcys142 retroviral vectors. Human apoE was detected by ELISA in the serum of apoE3, apoE2, and apoEcys142 mice as early as 4 weeks after bone marrow transplantation, and at 8 weeks, plasma apoE levels were 55.5±20.3, 50.5±8.7, and 15.3±7.3 µg/dL, respectively. In all groups, cholesterol levels increased with age but were not affected by apoE expression. As previously demonstrated, the lesion area in male apoE3 mice (3808±2224 µm²/section) was 40% smaller than that in control mice (6503±3475 µm²/section). In apoE2 mice, however, the lesion area was similar to that of controls (5991±2771 µm²/section), and apoEcys142 mice showed an unexpected and significant increase in lesion size (10 320±6128 µm²/section). Thus, transplantation with marrow transfected with receptor binding–defective apoE variants did not replicate the antiatherogenic effect of apoE3.

Conclusions— These data provide in vivo evidence suggesting that macrophage-derived apoE delays development of atherosclerosis through a receptor-dependent pathway.

Key Words: apolipoproteins • receptors • lipoproteins • proteoglycans

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