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* Vanderbilt University Medical Center, Departments of Medicine, Nashville, TN 37232
Pathology, Nashville, TN 37232
Pharmacology, Nashville, TN 37232
1 To whom correspondence should be addressed. e-mail: sergio.fazio{at}vanderbilt.edu or macrae.linton{at}vanderbilt.edu
We have previously reported that the introduction of macrophage apoE into mice lacking both apoE and the LDL receptor (apoE-/-/LDLR-/-) through bone marrow transplantation (apoE+/+/LDLR-/-
apoE-/-/LDLR-/-) produces progressive accumulation of apoE in plasma without affecting lipid levels. This model provides a tool to study the effects of physiologically regulated amounts of macrophage apoE on atherogenesis in hyperlipidemic animals. Ten-week-old male apoE-/-/LDLR-/- mice were transplanted with either apoE+/+/LDLR-/- (n = 11) or apoE-/-/LDLR-/- (n = 14) marrow. Although there were no differences between the two groups in lipid levels at baseline or at 5 and 9 weeks after transplantation, apoE levels in the apoE+/+LDLR-/-apoE-/-/LDLR-/- mice increased to 4 times the apoE levels of normal mice. This resulted in a 60% decrease in aortic atherosclerosis in the apoE+/+/LDLR-/-apoE-/-/LDLR-/- compared with the apoE-/-/LDLR-/-apoE-/-/LDLR-/- controls, (15,957 ± 1907 vs. 40,115 ± 8302 µm2 ± SEM, respectively). In a separate experiment, apoE+/+/LDLR-/- mice were transplanted with either apoE+/+/LDLR-/- or apoE-/-/LDLR-/- marrow and placed on a high-fat diet for 8 weeks. In the absence of macrophage apoE, lesion area was increased by 75% in the aortic sinus and by 56% in the distal aorta.
These data show that physiologic levels of macrophage apoE in the vessel wall are anti-atherogenic in conditions of severe hyperlipidemia and can affect later stages of plaque development.
Abbreviations: BMT, bone marrow transplant; HSPG, heparan sulfate proteoglycans; LDLR, low density lipoprotein receptor; LXR, liver X receptor; TNF
, tumor necrosis factor
Supplementary key words apolipoprotein E • low density lipoprotein receptor • hyperlipidemia • bone marrow transplant
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