Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice
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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, (15957 +/- 1907 vs. 40115 +/- 8302 micro m(2) +/- 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.
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Through bone marrow transplantation, the authors produced two types of chimeric mice expressing apoE exclusively from macrophages: apoE-/- mice, whose dyslipidemia is corrected by apoE expression; and apoE-/-/LDLR-/- DKO mice, whose dyslipidemia is not affected by apoE expression.
“Through bone marrow transplantation, we produced two types of chimeric mice expressing apoE exclusively from macrophages: 1 ) apoE Ϫ / Ϫ mice, whose dyslipidemia is corrected by apoE expression; and 2 ) apoE Ϫ / Ϫ /LDLR Ϫ / Ϫ double KO (DKO) mice, whose dyslipidemia is not affected by apoE expression ( 15,37 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [15]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredWe have previously reported that serum clearance of macrophage apoE is altered in these DKO mice resulting in accumulation of circulating apoE.
“We have previously reported that serum clearance of macrophage apoE is altered in these DKO mice resulting in accumulation of circulating apoE ( 15 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [15]
The Results (page unavailable) report that macrophage-derived apoE accumulated in the plasma of apoE/LDLR double-knockout mice after bone marrow transplantation. The paper does not directly report altered serum clearance of macrophage apoE; its discussion of impaired clearance concerns lipoproteins, so the claim’s proposed explanation is not fully supported. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe atheroprotective role of macrophage apoE has been well documented, with macrophage-derived apoE protecting against atherosclerosis during both early and late plaque development; protection remains even when expressed in low amounts and in the absence of changes in serum lipid levels.
“The atheroprotective role of macrophage apoE has been well documented, with macrophage-derived apoE being shown to protect against atherosclerosis during both early ( 12,13 ) and late plaque development ( 11 ); protection remains even when it is expressed in low amounts ( 14 ) and in the absence of changes in serum lipid levels ( 15 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [15]
It was previously shown that expression of apoE in DKO model does not reduce serum lipid levels, and that macrophage-expressed apoE can protect against atherosclerosis, even in the absence of cholesterol changes.
“It was previously shown that expression of apoE in this model does not reduce serum lipid levels, and that macrophage-expressed apoE can protect against atherosclerosis, even in the absence of cholesterol changes ( 15,37 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [15]
Cholesterol levels in DKO recipient mice did not decrease after apoE expression.
“As expected, cholesterol levels in DKO recipient mice did not decrease after apoE expression ( 15 ).”
From Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice (2014) · cites this paper as [15]
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Cites
Van Eck, M., Herijgers, N., Yates, J., Pearce, N. J., Hoogerbrugge, P. M., Groot, P. H. E., & Van Berkel, T. J. C. (1997) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.17.11.3117 · Cited by 96 · see citing works
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Research works printed but not linked: 3
- Fazio, S., V. R. Babaev, A. B. Murray, A. H. Hasty, K. J. Carter, L. A. Gleaves, J. B. Atkinson, and M. F. Linton. 1997. Increased athero- sclerosis in C57BL/6 mice reconstituted with apolipoprotein E null macrophages. Proc. Natl. Acad. Sci. USA. 94: 4647-4652.
- Laffitte, B. A., J. J. Repa, S. B. Joseph, D. C. Wilpitz, H. R. Kast, D. J. Mangelsdorf, and P. Tontonoz. 2001. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adi- pocytes. Proc. Natl. Acad. Sci. USA. 98: 507-512.
- Joyce, C. W., M. J. A. Amar, G. Lambert, B. L. Vaisman, B. Paigen, J. Najib-Fruchart, J. R. F. Hoyt, E. D. Neufeld, A. T. Remaley, D. S. Fredrickson, and J. H. B. Brewer. 2002. The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic ath- erosclerosis in C57BL/6 and apoE-knockout mice. Proc. Natl. Acad. Sci. USA. 99: 407-412.
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Apolipoprotein E–related glomerular disorders
Saito, T., Matsunaga, A., Fukunaga, M., Nagahama, K., Hara, S., & Muso, E. (2020) · Kidney International · doi:10.1016/j.kint.2019.10.031 · Cited by 77 · see citing works
Tavori, H., Fan, D., Giunzioni, I., Zhu, L., Linton, M. F., Fogo, A. B., & Fazio, S. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m049874 · Cited by 10 · see citing works
Self-citation
- Authors
- Fazio, S., Babaev, V. R., Burleigh, M. E., Major, A. S., Hasty, A. H., & Linton, M. F.
- Affiliations
- Vanderbilt University Medical Center (US)
- Corresponding author
- Fazio, Sergio
- Linton, MacRae F.
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 43
- Issue
- 10
- Pages
- 1602-1609
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2121342540
- Cited by
- 58
- References
- 1
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 3 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 2
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association
- Vanderbilt University
- National Institutes of Health (5f32hl010206-02)
- National Heart, Lung, and Blood Institute (R01HL057986, R01HL065709, HL57986, T32-HL-07411, HL 53989, T32HL007411, R01HL053989, HL10206-02)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- atherosclerosis, hyperlipidemia, LDL receptor deficiency, bone marrow transplantation, aortic plaque, high-fat diet, antiatherogenic effects, atherosclerotic lesion development
- MeSH terms
- Animals, Aorta, Apolipoproteins E, Arteriosclerosis, Bone Marrow Cells, Hyperlipidemias, Immunohistochemistry, Macrophages, Mice, Inbred C57BL, Blotting, Western, Bone Marrow Transplantation, In Situ Hybridization, Mice, Knockout, Mice
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