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

T Cyrus1, J L Witztum, D J Rader

  • 1Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

The Journal of Clinical Investigation
|June 8, 1999

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View abstract on PubMed

Summary
This summary is machine-generated.

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  • Biomedical And Clinical Sciences
  • Oncology And Carcinogenesis
  • Predictive And Prognostic Markers
  • Disruption Of The 12/15-lipoxygenase Gene Diminishes Atherosclerosis In Apo E-deficient Mice.

    • The study shows that inhibiting 12/15-lipoxygenase reduces atherosclerosis development in mice. This enzyme plays a key role in the inflammatory disease process, suggesting a new therapeutic target for atherosclerosis.

    Area of Science:

    • Cardiovascular Biology
    • Inflammation Research
    • Lipid Metabolism

    Background:

    • Atherosclerosis is an inflammatory disease involving oxidized LDL and foam cell formation.
    • Lipoxygenases are implicated in the oxidative modification of LDLs.
    • The specific role of macrophage-expressed lipoxygenases in atherosclerosis in vivo is not well understood.

    Purpose of the Study:

    • To investigate the in vivo role of 12/15-lipoxygenase in atherogenesis.
    • To determine if inhibiting 12/15-lipoxygenase impacts atherosclerosis development and associated autoantibodies.

    Main Methods:

    • Generation of 12/15-lipoxygenase knockout mice crossbred with apo E-deficient mice (apo E-/-/L-12LO-/-).
    • Assessment of atherosclerotic lesion extent in whole-aorta en face preparations at 15 weeks and 1 year.
    • Measurement of plasma IgG autoantibodies to oxidized LDL epitopes.
    • Analysis of cholesterol, triglyceride, and lipoprotein levels.

    Main Results:

    • Significantly reduced atherosclerotic lesion area in apo E-/-/L-12LO-/- mice compared to controls (198 +/- 60 microm2 vs. 15,700 +/- 2,688 microm2).
    • Diminished plasma IgG autoantibodies to oxidized LDL epitopes in knockout mice.
    • Similar lipid profiles between knockout and control apo E-deficient mice, indicating lesion reduction is independent of overall lipid levels.
    • Reduced lesion development observed even at 1 year of age.

    Conclusions:

    • 12/15-lipoxygenase plays a significant role in the pathogenesis of atherosclerosis in vivo.
    • Inhibition of 12/15-lipoxygenase can substantially decrease atherosclerosis progression.
    • Targeting 12/15-lipoxygenase may represent a novel therapeutic strategy for atherosclerosis.

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