Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice
Open accessAbstract
apoE deficiency causes hyperlipidemia and premature atherosclerosis. To determine if macrophage-specific expression of apoE would decrease the extent of atherosclerosis, we expressed human apoE in macrophages of apoE-null mice (apoE-/-) and assessed the effect on lipid accumulation in cells of the arterial wall. Macrophage-specific expression of human apoE in normal mice was obtained by use of the visna virus LTR. These animals were bred with apoE-/- mice to produce animals hemizygous for expression of human apoE in macrophages in the absence of murine apoE (apoE-/-,hTgE+/0). Low levels of human apoE mRNA were present in liver and spleen and high levels in lung and peritoneal macrophages. Human apoE was secreted by peritoneal macrophages and was detected in Kupffer cells of the liver. Human apoE in the plasma of apoE-/-,hTgE+/0 mice (n = 30) was inversely correlated (P < 0.005) with the plasma cholesterol concentration. After 15 wk on a normal chow diet, atherosclerosis was assessed in apoE-/-,hTgE+/0 animals and in apoE-/-,hTgE0/0 littermates matched for plasma cholesterol level (approximately 450 mg/dl) and lipoprotein profile. There was significantly less atherosclerosis in both the aortic sinus and in the proximal aorta (P < 0.0001) in the animals expressing the human apoE transgene. In apo-E-/-,hTgE+/0 animals, which had detectable atherosclerotic lesions, human apoE was detected in the secretory apparatus of macrophage-derived foam cells in the arterial wall. The data demonstrate that expression of apoE by macrophages is antiatherogenic even in the presence of high levels of atherogenic lipoproteins. The data suggest that apoE prevents atherosclerosis by promoting cholesterol efflux from cells of the arterial wall.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The 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 [12]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Plump, A. S., Smith, J. D., Hayek, T., Aalto-Setälä, K., Walsh, A., Verstuyft, J. G., Rubin, E. M., & Breslow, J. L. (1992) · Cell · doi:10.1016/0092-8674(92)90362-g · Cited by 2,263 · see citing works
ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree.
Nakashima, Y., Plump, A. S., Raines, E. W., Breslow, J. L., & Ross, R. (1994) · Arteriosclerosis and Thrombosis: A Journal of Vascular Biology · doi:10.1161/01.atv.14.1.133 · Cited by 1,693 · see citing works
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation.
Linton, M. F., Gish, R., Hubl, S. T., Bütler, E., Esquivel, C., Bry, W. I., Boyles, J. K., Wardell, M. R., & Young, S. G. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115288 · Cited by 367 · see citing works
Flagged first, then by citations
Research works printed but not linked: 7
- Pitas, R. E., T. L. Innerarity, K. S. Arnold, and R. W. Mahley. 1979. Rate and equilibrium constants for binding of apo-E HDL, (a cholesterol-induced lipoprotein) and low density lipoproteins to human fibroblasts: Evidence for multi- ple receptor binding of apo-E HDL,. Proc. Natl. Acad. Sci. USA. 76:2311-2315.
- Yamada, N., D. M. Shames, J. B. Stoudemire, and R. J. Havel. 1986. Metabolism of lipoproteins containing apolipoprotein B-100 in blood plasma of rabbits: heterogeneity related to the presence of apolipoprotein E. Proc. Natl. Acad. Sci. USA. 83:3479-3483.
- Piedrahita, J. A., S. H. Zhang, J. R. Hagaman, P. M. Oliver, and N. Maeda. 1992. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc. Natl. Acad. Sci. USA. 89:4471- 4475.
- Hogan, B., F. Costantini, and E. Lacy. 1986. Manipulating the Mouse Embryo. A Laboratory Manual. Cold Spring Harbor Press, Cold Spring Harbor, NY. 332 pp.
- Shimano, H., N. Yamada, M. Katsuki, M. Shimada, T. Gotoda, K. Harada, T. Murase, C. Fukazawa, F. Takaku, and Y. Yazaki. 1992. Overexpression of apolipoprotein E in transgenic mice: marked reduction in plasma lipoproteins except high density lipoprotein and resistance against diet-induced hypercholester- olemia. Proc. Natl. Acad. Sci. USA. 89:1750-1754.
- Plump, A. S., C. J. Scott, and J. L. Breslow. 1994. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atheroscle- rosis in the apolipoprotein E-deficient mouse. Proc. Natl. Acad. Sci. USA. 91:9607-9611.
- Huang, Y., A. von Eckardstein, S. Wu, N. Maeda, and G. Assmann. 1994. A plasma lipoprotein containing only apolipoprotein E and with y mobility on electrophoresis releases cholesterol from cells. Proc. NatI. Acad. Sci. USA. 91:1834-1838.
Cited by
Sorted by citations
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836 · see citing works
Self-citationBorén, J., Chapman, M. J., Krauss, R. M., Packard, C. J., Bentzon, J. F., Binder, C. J., Daemen, M. J., Demer, L. L., Hegele, R. A., Nicholls, S. J., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz962 · Cited by 1,601 · see citing works
Holtzman, D. M., Bales, K. R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A. M., Chang, L. K., Sun, Y., & Paul, S. M. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6179 · Cited by 349 · see citing works
Apolipoprotein E isoforms and lipoprotein metabolism
Phillips, M. C. (2014) · IUBMB Life · doi:10.1002/iub.1314 · Cited by 328 · see citing works
Getz, G. S., & Reardon, C. A. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.306874 · Cited by 198 · see citing works
Macrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation
Yancey, P. G., Blakemore, J., Ding, L., Fan, D., Overton, C. D., Zhang, Y., Linton, M. F., & Fazio, S. (2010) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.109.202051 · Cited by 168 · see citing works
ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age
Mooijaart, S. P., Berbée, J. F. P., van Heemst, D., Havekes, L. M., de Craen, A. J. M., Slagboom, P. E., Rensen, P. C. N., & Westendorp, R. G. J. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030176 · Cited by 129 · see citing works
Regulated expression of apolipoprotein E by human retinal pigment epithelial cells
Ishida, B. Y., Bailey, K. R., Duncan, K. G., Chalkley, R. J., Burlingame, A. L., Kane, J. P., & Schwartz, D. M. (2004) · Journal of Lipid Research · doi:10.1194/jlr.m300306-jlr200 · Cited by 111 · see citing works
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
Hara, M., Matsushima, T., Satoh, H., Iso-o, N., Noto, H., Togo, M., Kimura, S., Hashimoto, Y., & Tsukamoto, K. (2003) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000054199.78458.4b · Cited by 53 · see citing works
Evidence for differential effects of apoE3 and apoE4 on HDL metabolism
Hopkins, P. C. R., Huang, Y., McGuire, J. G., & Pitas, R. E. (2002) · Journal of Lipid Research · doi:10.1194/jlr.m200172-jlr200 · Cited by 31 · see citing works
Self-citationTavori, 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
- Authors
- Bellosta, S., Mahley, R. W., Sanan, D. A., Murata, J., Newland, D. L., Taylor, J. M., & Pitas, R. E.
- Affiliations
- University of California, San Francisco (US)
- Gladstone Institutes (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1995-11-01
- Volume
- 96
- Issue
- 5
- Pages
- 2170-2179
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC185866
- OpenAlex
- W2134010411
- Cited by
- 284
- References
- 4
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 10 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 4 · 2012: 8
- FWCI
- 13.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (5p01hl047660-10)
- National Heart, Lung, and Blood Institute (HL-47660)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, macrophages, atherosclerosis, ApoE-null mice, transgenic mice, hypercholesterolemia, foam cells, cholesterol efflux, Kupffer cells, peritoneal macrophages, antiatherogenic effects, serum cholesterol
- MeSH terms
- Animals, Apolipoproteins E, Arteriosclerosis, Cells, Cultured, Cholesterol, Female, Foam Cells, Humans, Hypercholesterolemia, Macrophages, Male, Mice, Transgenic, Gene Expression, Gene Transfer Techniques, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
