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-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.
Zhao
Lei
L
Institute of Translational Medicine and Therapeutics, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA. leizhao@spirit.gcrc.upenn.edu
Praticò
Domenico
D
Rader
Daniel J
DJ
Funk
Colin D
CD
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics*; D050197:Atherosclerosis / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology
D001057:Apolipoproteins E; D014810:Vitamin E; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase