12/15-lipoxygenase deficiency results in delayed atherosclerotic lesion initiation in vivo

12/15-Lipoxygenase (12/15-LO) has been implicated in the oxidative modification of lo cv density lipoprotein (LDL) and in atherogenesis. The relative contribution of macrophage-expressed 12/15-LO to atherogenesis in vivo remains controversial. 12/15-LO deficient (L-12LO(-/-)) mice, generated by targeted gene disruption in our laboratory, were crossed with atherosclerosis-prone apolipoprotein E deficient (apoE(-/-)) mice. Lesion areas in the whole aortas (en face preparations) developed earlier in apo E-/-/L-12LO(-/-) mice, than in apoE(-/-)/L-12LO(-/-) double-knockout mice. At 10 weeks, lesion areas were 677 +/- 365 vs. 52 +/- 52 mu m(2) (mean +/- SEM, n = 10, P=0.03 (Mann-Whitney test)) respectively, and lesion progression was enhanced in the heterozygous mice as compared to the double-knockout mice (258696 +/- 24374 vs. 108075 +/- 11964 mu m(2), n = 9, P = 0.002) at 15 months of age. Lipoprotein oxidation via enzymatic action of 12/15-LO is a major component of atherogenesis in apoE(-/-) mice, and this animal model provides in vivo evidence for the importance of 12/15-LO in the initiation of atherosclerotic lesions.