Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice

Atherosclerosis may be viewed as an inflammatory disease process that inclu des early oxidative modification of LDLs, leading to foam cell formation. T his "oxidation hypothesis" has gained general acceptance in recent years, a nd evidence for the role of lipoxygenases in initiation of, or participatio n in, the oxidative process is accumulating. However, the relative contribu tion of macrophage-expressed lipoxygenases to atherogenesis in vivo remains unknown. Here, we provide in vivo evidence for the role of 12/15-lipoxygen ase in atherogenesis and demonstrate diminished plasma IgG autoantibodies t o oxidized LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis-prone apo E-deficient mice (apo E-/-/L-12LO(-/-)). In chow- fed 15-week-old apo E-/-/L-12LO(-/-) mice, the extent of lesions in whole-a orta en face preparations (198 +/- 60 mu m(2)) was strongly reduced (P < 0. 001, n = 12) when compared with 12/15-lipoxygenase-expressing controls (apo E-/-/L-12LO(+/+)), which showed areas of lipid deposition (15,700 +/- 2,68 8 mu m(2)) in the lesser curvature of the aortic arch, branch points, and i n the abdominal aorta. These results were observed despite cholesterol, tri glyceride, and lipoprotein levels that were similar to those in apo E-defic ient mice. Evidence for reduced lesion development was observed even at 1 y ear of age in apo E-/-/L-12LO(-/-) mice. The combined data indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and suggest t hat inhibition of this enzyme may decrease disease progression.