Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice.
Oxidative modification of low density lipoprotein (LDL) has been implicated in atherogenesis. Evidence consistent with this hypothesis includes the presence of oxidized lipids in atherosclerotic lesions, the newly discovered biological properties conferred on LDL by oxidation and the acceleration of atherogenesis by in vivo delivery of the gene for 15-lipoxygenase, an oxidizing enzyme present in atherosclerotic lesions. However, it is still unknown whether oxidative stress actually coincides with the evolution of the disease or whether it is of functional relevance to atherogenesis in vivo. Isoprostanes are products of arachidonic acid catalyzed by free radicals, which reflect oxidative stress and lipid peroxidation in vivo. Elevation of tissue and urinary isoprostanes is characteristic of human atherosclerosis. Here, deficiency in apolipoprotein E in the mouse (apoE-/-) resulted in atherogenesis and an increase in iPF2alpha-VI, an F2-isoprostane, in urine, plasma and vascular tissue. Supplementation with vitamin E significantly reduced isoprostane generation, but had no effect on plasma cholesterol levels in apoE-/- mice. Aortic lesion areas and iPF2alpha-VI levels in the arterial wall were also reduced significantly by vitamin E. Our results indicate that oxidative stress is increased in the apoE-/- mouse, is of functional importance in the evolution of atherosclerosis and can be suppressed by oral administration of vitamin E.
The Center for Experimental Therapeutics and the Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia 19104, USA.
D
D
Praticò
R K
RK
Tangirala
D J
DJ
Rader
J
J
Rokach
G A
GA
FitzGerald
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D015237:Dinoprost / Q000032:analysis*; D007536:Isomerism; D051379:Mice; D008817:Mice, Mutant Strains; D018384:Oxidative Stress; D014810:Vitamin E / Q000097:blood / Q000494:pharmacology*
D001057:Apolipoproteins E; D014810:Vitamin E; D002784:Cholesterol; D015237:Dinoprost