Cited by 528Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismAntioxidant Activity and Oxidative Stress

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Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice

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Cyrus, Tillmann, Witztum, Joseph L., Rader, Daniel J., Tangirala, Rajendra, Fazio, Sergio, Linton, MacRae F., Funk, Colin D.·1999·Journal of Clinical Investigation

DOI 10.1172/jci5897PMC PMC408369

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Abstract

Atherosclerosis may be viewed as an inflammatory disease process that includes early oxidative modification of LDLs, leading to foam cell formation. This "oxidation hypothesis" has gained general acceptance in recent years, and evidence for the role of lipoxygenases in initiation of, or participation in, the oxidative process is accumulating. However, the relative contribution of macrophage-expressed lipoxygenases to atherogenesis in vivo remains unknown. Here, we provide in vivo evidence for the role of 12/15-lipoxygenase in atherogenesis and demonstrate diminished plasma IgG autoantibodies to oxidized LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis-prone apo E-deficient mice (apo E-/-/L-12LO-/-). In chow-fed 15-week-old apo E-/-/L-12LO-/- mice, the extent of lesions in whole-aorta en face preparations (198 +/- 60 microm2) was strongly reduced (P < 0.001, n = 12) when compared with 12/15-lipoxygenase-expressing controls (apo E-/-/L-12LO+/+), which showed areas of lipid deposition (15,700 +/- 2,688 microm2) in the lesser curvature of the aortic arch, branch points, and in the abdominal aorta. These results were observed despite cholesterol, triglyceride, and lipoprotein levels that were similar to those in apo E-deficient mice. Evidence for reduced lesion development was observed even at 1 year of age in apo E-/-/L-12LO-/- mice. The combined data indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and suggest that inhibition of this enzyme may decrease disease progression.

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Authors: Cyrus, T., Witztum, J. L., Rader, D. J., Tangirala, R., Fazio, S., Linton, M. F., & Funk, C. D.
Affiliations: University of Pennsylvania (US)
University of California San Diego (US)
Vanderbilt University (US)
Corresponding author: Funk, Colin D.
ORCID: Witztum, Joseph L.
Rader, Daniel J.
Fazio, Sergio
Linton, MacRae F.
Funk, Colin D.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1999-06-01
Volume: 103
Issue: 11
Pages: 1597-1604
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci5897
PMC: PMC408369
OpenAlex: W2149303684
Cited by: 523
References: 63
Citations by year: 2026: 5 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 10 · 2021: 7 · 2020: 4 · 2019: 12 · 2018: 12 · 2017: 13 · 2016: 17 · 2015: 18 · 2014: 19 · 2013: 19 · 2012: 20
FWCI: 14.13
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (GM 15431)
National Heart, Lung, and Blood Institute (R01HL053558, R01HL059694, HL59694, HL-53558)
National Institute of General Medical Sciences (GM 15431, P50GM015431, P01GM015431)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords: 12/15-lipoxygenase, atherosclerosis, oxidized LDL, IgG autoantibodies, macrophages, foam cell formation, LDL oxidation, aortic lesions, atherogenesis
MeSH terms: Animals, Aorta, Apolipoproteins E, Arachidonate 12-Lipoxygenase, Arachidonate 15-Lipoxygenase, Arteriosclerosis, Autoantibodies, Female, Lipoproteins, LDL, Male, Mice, Inbred C57BL, Mice, Knockout, Lipid Metabolism, Mice

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Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice

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