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
Summary
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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