(Circulation. 2001;103:2277.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Absence of 12/15-Lipoxygenase Expression Decreases Lipid Peroxidation and Atherogenesis in Apolipoprotein E–Deficient Mice
From the Center for Experimental Therapeutics (T.C., D.P., L.Z., G.A.F., C.D.F.) and the Department of Medicine (D.J.R.), University of Pennsylvania, Philadelphia; the Department of Medicine, University of California–San Diego (J.L.W.); and the Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne (J.R.).
Correspondence to Colin D. Funk, Center for Experimental Therapeutics, University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19104-6160. E-mail colin{at}spirit.gcrc.upenn.edu
Background—The enzyme 12/15-lipoxygenase (12/15-LO) has been implicated in the oxidative modification of LDL. In a murine model, we tested the hypothesis that deletion of 12/15-LO decreases atherogenesis by reducing oxidant stress, as measured by 2 indices of lipid peroxidation: isoprostane generation and autoantibody formation to malondialdehyde (MDA)-LDL, an epitope of LDL formed as a result of oxidative modification.
Methods and
Results—12/15-LO–deficient
(12/15-LO-/-) mice were crossed with
apolipoprotein E–deficient (apoE-/-)
mice. At 10 weeks of age, atherosclerotic lesion initiation was
significantly delayed in the double-knockout mice. The rate of lesion
progression was diminished at 8 and 12 months, and even at 15 months,
lesion size was reduced 50%
(P<0.0005) compared with
control apoE-/- mice. The urinary and
plasma levels of the specific isoprostane
8,12-iso-iPF2
-VI, as well as IgG
autoantibodies against MDA-LDL, were significantly reduced in the
double-deficient mice in parallel with decreased
atherosclerosis at all time points from 10 weeks to 15
months of age compared with apoE-/-
controls.
Conclusions—Enzymatic action of 12/15-LO contributes significantly to atherosclerotic lesion initiation and propagation in this murine model. Strong positive correlations exist between lesion size, isoprostane levels, and MDA-LDL autoantibodies, providing in vivo evidence for an enzymatic (12/15-LO) component to lipid peroxidation and atherogenesis.
Key Words: atherosclerosis • enzymes • lipoxygenase • lipids
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