Background Human 15-lipoxygenase (LO) and its murine analogue 12/15-LO are capable of directly oxidizing esterified fatty acids in lipoproteins and phospholipids. Because these oxidized products possess atherogenic properties, it was suggested that LOs may be involved in enhancing atherogenesis. Previous in vivo tests of the role of LOs in atherogenesis animal models, however, have yielded conflicting results.

Methods and Results Aiming to study the role of the 12/15-LO in murine atherogenesis, we crossed LDL-receptor–deficient mice (LDL-R^−/−) with 12/15-LO–knockout mice and evaluated plaque formation 3 to 18 weeks after initiation of a high-fat diet. Atherosclerotic lesions were considerably reduced in the LDL-R/12/15-LO–double-knockout mice compared with LDL-R^−/− mice at 3, 9, 12, and 18 weeks, at the aortic root as well as throughout the aorta. The cellular composition of plaques from mice deficient in 12/15-LO did not differ with respect to macrophage and T-lymphocyte content compared with plaques from 12/15-LO littermates.

Conclusions 12/15-LO plays a dominant role in promoting atherogenesis in LDL-R^−/− mice.