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

摘要

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 athero-genesis 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 (2000IU/kg). Plasma Vitamin E, urinary 8,12-iso-iPF_(2alpha)-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-iPF_(2alpha)-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.