alexa Absence of 12 15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice.
Immunology

Immunology

Journal of Cytokine Biology

Author(s): Cyrus T, Pratic D, Zhao L, Witztum JL, Rader DJ,

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Abstract 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-iPF(2alpha)-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.
This article was published in Circulation and referenced in Journal of Cytokine Biology

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