12/15-Lipoxygenase gene disruption and Vitamin E administration diminish atherosclerosis and oxidative stress in apolipoprotein E deficient mice through a final common pathway

Studies in mouse models of atherosclerosis using 12/15-lipoxygenase (12/15-LO) gene disruption and transgenic overexpression demonstrate a pro-oxidative, pro-atherogenic role for this pathway. Vitamin E has been shown to suppress lipid peroxidation and reduce early atherogenesis in several mouse models, although conflicting results from several clinical trials have been reported. ApoE−/− and apoE−/−/12/15-LO−/− mice were maintained on normal chow diet with or without Vitamin E supplement (2000 IU/kg). Plasma Vitamin E, urinary 8,12-iso-iPF2α-VI and aortic lesion quantitation were assessed. Plasma Vitamin E levels significantly increased upon Vitamin E diet supplementation. 12/15-LO gene disruption resulted in significantly reduced aortic lesions and decreased urinary 8,12-iso-iPF2α-VI levels in apoE−/− mice, similar to Vitamin E administration in the absence of 12/15-LO gene disruption. However, Vitamin E dietary supplementation did not afford additive or synergistic protection in apoE−/−/12/15-LO−/− mice. These results suggest that early 12/15-LO-mediated lipid peroxidation triggers ensuing non-enzymatic peroxidation that is susceptible to Vitamin E antioxidant action in a common pathway of atherogenesis.