Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice
Abstract
We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor–null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined. The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor–null (LDLR −/− ) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold; P <0.0005) in aortic lesion development, similar to the CON6 mice. Immunohistochemistry revealed that 5-LO was abundantly expressed in atherosclerotic lesions of apoE − /− and LDLR −/− deficient mice, appearing to colocalize with a subset of macrophages but not with all macrophage-staining regions. When bone marrow from 5-LO +/− mice was transplanted into LDLR −/− , there was a significant reduction in atherogenesis, suggesting that macrophage 5-LO is responsible, at least in part, for the effect on atherosclerosis. These results indicate that 5-LO contributes importantly to the atherogenic process and they provide strong presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis in CON6 mice.
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?
Several examples of biological oxidations mediated by the bicarbonate anion, in particular through interactions with peroxynitrite, have been reported.
“Several examples of biological oxidations mediated by the bicarbonate anion, in particular through interactions with peroxynitrite, have been reported in the literature [e.g., (46, 635, 918, 1056)].”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [635]
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
Lusis, A. J. (2000) · Nature · doi:10.1038/35025203 · Cited by 4,880 · see citing works
Self-citationProstaglandins and Leukotrienes: Advances in Eicosanoid Biology
Funk, C. D. (2001) · Science · doi:10.1126/science.294.5548.1871 · Cited by 3,817 · see citing works
Self-citationStimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor
Tontonoz, P., Hu, E., & Spiegelman, B. M. (1994) · Cell · doi:10.1016/0092-8674(94)90006-x · Cited by 3,533 · see citing works
PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL
Tontonoz, P., Nagy, L., Alvarez, J. G. A., Thomázy, V. A., & Evans, R. M. (1998) · Cell · doi:10.1016/s0092-8674(00)81575-5 · Cited by 1,800 · see citing works
Atherosclerosis is an inflammatory disease
Ross, R. (1999) · American Heart Journal · doi:10.1016/s0002-8703(99)70266-8 · Cited by 1,458 · see citing works
A PPARγ-LXR-ABCA1 Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis
Chawla, A., Boisvert, W. A., Lee, C.-H., Laffitte, B. A., Barak, Y., Joseph, S. B., Liao, D., Nagy, L., Edwards, P. A., Curtiss, L. K., et al. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00164-2 · Cited by 1,347 · see citing works
The PPARα–leukotriene B4 pathway to inflammation control
Devchand, P. R., Keller, H., Peters, J. M., Vazquez, M., Gonzalez, F. J., & Wahli, W. (1996) · Nature · doi:10.1038/384039a0 · Cited by 1,345 · see citing works
A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis
Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y., & Shimizu, T. (1997) · Nature · doi:10.1038/42506 · Cited by 971 · see citing works
Fruchart, J.-C., Duriez, P., & Staels, B. (1999) · Current Opinion in Lipidology · doi:10.1097/00041433-199906000-00007 · Cited by 425 · see citing works
Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene
Chen, X.-S., Shelter, J. R., Johnson, E. N., & Funk, C. D. (1994) · Nature · doi:10.1038/372179a0 · Cited by 414 · see citing works
Self-citationRole of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice.
Qiao, J. H., Tripathi, J., Mishra, N. K., Cai, Y., Tripathi, S., Wang, X. P., Imes, S., Fishbein, M. C., Clinton, S. K., Libby, P., et al. (1997) · Europe PMC (PubMed Central) · Cited by 327 · see citing works
Self-citationLee, H., Shi, W., Tontonoz, P., Wang, S., Subbanagounder, G., Hedrick, C. C., Hama, S. Y., Borromeo, C. M., Evans, R. M., Berliner, J. A., et al. (2000) · Circulation Research · doi:10.1161/01.res.87.6.516 · Cited by 291 · see citing works
Goetzl, E. J., An, S., & Smith, W. L. (1995) · The FASEB Journal · doi:10.1096/fasebj.9.11.7649404 · Cited by 275 · see citing works
Ligand Selectivity of the Peroxisome Proliferator-Activated Receptor α
Lin, Q., Ruuska, S. E., Shaw, N. S., Dong, D., & Noy, N. (1999) · Biochemistry · doi:10.1021/bi9816094 · Cited by 263 · see citing works
Leukotriene B4: Metabolism and Signal Transduction
Yokomizo, T., Izumi, T., & Shimizu, T. (2001) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.2168 · Cited by 231 · see citing works
Matsukawa, A., Hogaboam, C. M., Lukacs, N. W., Lincoln, P., Strieter, R. M., & Kunkel, S. L. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.11.6148 · Cited by 229 · see citing works
Tager, A. M., Dufour, J. H., Goodarzi, K., Bercury, S. D., von Andrian, U. H., & Luster, A. D. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.3.439 · Cited by 195 · see citing works
Haribabu, B., Verghese, M. W., Steeber, D. A., Sellars, D. D., Bock, C. B., & D, R. S. M. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.3.433 · Cited by 175 · see citing works
Determinants of Atherosclerosis Susceptibility in the C3H and C57BL/6 Mouse Model
Shi, W., Wang, N. J., Shih, D. M., Sun, V. Z., Wang, X., & Lusis, A. J. (2000) · Circulation Research · doi:10.1161/01.res.86.10.1078 · Cited by 138 · see citing works
Self-citation12/15-Lipoxygenase, Oxidative Modification of LDL and Atherogenesis
Cyrus, C. (2001) · Trends in Cardiovascular Medicine · doi:10.1016/s1050-1738(01)00096-2 · Cited by 125 · see citing works
Genetic Locus in Mice That Blocks Development of Atherosclerosis Despite Extreme Hyperlipidemia
Mehrabian, M., Wong, J., Wang, X., Jiang, Z., Shi, W., Fogelman, A. M., & Lusis, A. J. (2001) · Circulation Research · doi:10.1161/hh1401.093458 · Cited by 84 · see citing works
Self-citationO’Flaherty, J. T., Kuroki, M., Nixon, A. B., Wijkander, J., Yee, E., Lee, S. L., Smitherman, P. K., Wykle, R. L., & Daniel, L. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.30.17821 · Cited by 80 · see citing works
Sozzani, S., Zhou, D., Locati, M., Bernasconi, S., Luini, W., Mantovani, A., & O’Flaherty, J. T. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.10.4664 · Cited by 79 · see citing works
Receptors for the 5-Oxo Class of Eicosanoids in Neutrophils
O’Flaherty, J. T., Taylor, J. S., & Thomas, M. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.32535 · Cited by 66 · see citing works
Synthesis of 5-oxo-6,8, 11, 14-eicosatetraenoic acid by human monocytes and lymphocytes
Zhang, Y., Styhler, A., & Powell, W. S. (1996) · Journal of Leukocyte Biology · doi:10.1002/jlb.59.6.847 · Cited by 45 · see citing works
Lepley, R. A., & Fitzpatrick, F. A. (1998) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1998.0744 · Cited by 42 · see citing works
Patterson, C., Madamanchi, N. R., & Runge, M. S. (2000) · Circulation Research · doi:10.1161/01.res.87.12.1074 · Cited by 41 · see citing works
5-Lipoxygenase and Leukotrienes: Transgenic Mouse and Nuclear Targeting Studies
Funk, C. D., & Chen, X. (2000) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.161.supplement_1.ltta-24 · Cited by 35 · see citing works
Self-citationSequestration of aggregated LDL by macrophages studied with freeze-etch electron microscopy
Haberland, M. E., Mottino, G. A., Le, M. M., & Frank, J. S. (2001) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)31170-6 · Cited by 29 · see citing works
HETEs and coronary artery endothelial cells: metabolic and functional interactions
Gordon, E. E. I., Gordon, J. A., & Spector, A. A. (1991) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1991.261.4.c623 · Cited by 25 · see citing works
Lipoxygenases and their Metabolites
(1999) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-4861-4 · Cited by 25 · see citing works
Zimpfer, U., Dichmann, S., Termeer, C., et al. (2000) · Inflammation Research · doi:10.1007/s000110050641 · Cited by 24 · see citing works
Lipoxygenases and their metabolites : biological functions
Nigam, S., Pace-Asciak, C. R., & Functions, T. M. B. (1999) · Kluwer eBooks · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Antiinflammatory Properties of HDL
Barter, P. J., Nicholls, S., Rye, K.-A., Anantharamaiah, G. M., Navab, M., & Fogelman, A. M. (2004) · Circulation Research · doi:10.1161/01.res.0000146094.59640.13 · Cited by 1,394 · see citing works
Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease
Haeggström, J. Z., & Funk, C. D. (2011) · Chemical Reviews · doi:10.1021/cr200246d · Cited by 875 · see citing works
Self-citationReactive oxygen species in cardiovascular disease
Sugamura, K., & Keaney (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.05.004 · Cited by 769 · see citing works
The macrophage foam cell as a target for therapeutic intervention
Li, A. C., & Glass, C. K. (2002) · Nature Medicine · doi:10.1038/nm1102-1235 · Cited by 700 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Translating molecular discoveries into new therapies for atherosclerosis
Rader, D. J., & Daugherty, A. (2008) · Nature · doi:10.1038/nature06796 · Cited by 515 · see citing works
Merched, A. J., Ko, K., Gotlinger, K. H., Serhan, C. N., & Chan, L. (2008) · The FASEB Journal · doi:10.1096/fj.08-112201 · Cited by 414 · see citing works
The role of non-resolving inflammation in atherosclerosis
Kasikara, C., Doran, A. C., Cai, B., & Tabas, I. (2018) · Journal of Clinical Investigation · doi:10.1172/jci97950 · Cited by 266 · see citing works
New insights on oxidative stress in the artery wall
STOCKER, R., & KEANEY, J. F. (2005) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2005.01370.x · Cited by 188 · see citing works
Atherosclerotic lesions in mouse and man: is it the same disease?
Bentzon, J. F., & Falk, E. (2010) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32833ded6a · Cited by 147 · see citing works
F2-isoprostanes as indices of lipid peroxidation in inflammatory diseases
Praticò, D., Rokach, J., Lawson, J., & FitzGerald, G. A. (2004) · Chemistry and Physics of Lipids · doi:10.1016/j.chemphyslip.2003.09.012 · Cited by 120 · see citing works
The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis
LOTZER, K., FUNK, C., & HABENICHT, A. (2005) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2005.07.001 · Cited by 108 · see citing works
Self-citationStored Iron and Vascular Reactivity
Sullivan, J. L. (2005) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000174124.20147.22 · Cited by 41 · see citing works
Genomics and Cardiovascular Drug Development
Plump, A. S., & Lum, P. Y. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2008.11.050 · Cited by 31 · see citing works
- Authors
- Mehrabian, M., Allayee, H., Wong, J., Shih, W., Wang, X.-P., Shaposhnik, Z., Funk, C. D., & Lusis, A. J.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Circulation Research
- Published
- 2002-07-26
- Volume
- 91
- Issue
- 2
- Pages
- 120-126
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2108014410
- Cited by
- 422
- References
- 33
- Citations by year
- 2025: 6 · 2024: 5 · 2023: 7 · 2022: 9 · 2021: 3 · 2020: 6 · 2019: 14 · 2018: 9 · 2017: 6 · 2016: 11 · 2015: 14 · 2014: 12 · 2013: 12 · 2012: 24
- FWCI
- 11.09
- Type
- journal article
- Language
- en
- Update notices
- correction (2002-10-18)
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (30568, HL30568)
- National Heart, Lung, and Blood Institute (HL3 0568, P01HL030568)
- National Institute of General Medical Sciences (5-T32-GM08243-15, T32GM008243)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- 5-lipoxygenase, atherosclerosis susceptibility, mouse chromosome 6, LDL receptor-null mice, hypercholesterolemia, leukotriene biosynthesis, macrophages, aortic atherosclerotic lesions, bone marrow transplantation, ApoE-deficient mice
- MeSH terms
- Alleles, Animals, Arachidonate 5-Lipoxygenase, Arteriosclerosis, Insulin, Macrophages, Mice, Inbred C57BL, Receptors, LDL, RNA, Messenger, Bone Marrow Transplantation, Mice, Knockout, Amino Acid Substitution, Genetic Predisposition to Disease, Mice, Congenic, 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
