Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein E-deficient mice

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 hypothe sis that deletion of 12/15-LO decreases atherogenesis by reducing oxidant s tress, as measured by 2 indices of lipid peroxidation: isoprostane generati on and autoantibody formation to malondialdehyde (MDA)-LDL, an epitope of L DL 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, atheroscl erotic lesion initiation was significantly delayed in the double-knockout m ice. 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 con trol apoE(-/-) mice. The urinary and plasma levels of the specific isoprost ane 8,12-iso-iPF(2<alpha>)-VI, as well as IgG autoantibodies against MDA-LD L, 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 ather osclerotic lesion initiation and propagation in this murine model. Strong p ositive 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.