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Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice

Nature Medicine volume 4, pages 1189–1192 (1998)Cite this article

Abstract

Oxidative modification of low density lipoprotein (LDL) has been implicated in atherogenesis 1 . Evidence consistent with this hypothesis includes the presence of oxidized lipids in atherosclerotic lesions 2, 3 , the newly discovered biological properties conferred on LDL by oxidation 1, 4 and the acceleration of atherogenesis by in vivo delivery of the gene for 15-lipoxygenase 5 , an oxidizing enzyme present in atherosclerotic lesions 6 . 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 7 . Elevation of tissue and urinary isoprostanes is characteristic of human atherosclerosis 8, 9 . Here, deficiency in apolipoprotein E in the mouse (apoE –/– ) resulted in atherogenesis and an increase in iPF 2α -VI, an F 2 -isoprostane 10 , 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 iPF 2α -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.

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Figure 1: Time course of iPF2α-VI urinary excretion (a) and plasma levels (b) in apoE–/– mice fed normal chow (▪) or chow supplemented with vitamin E (2000 I.
Figure 2: Plasma vitamin E concentration (a), total plasma cholesterol (b) and triglyceride levels (c) in apoE–/– mice fed normal chow (▪) or chow supplemented with vitamin E (2000 I.
Figure 3: Correlations between plasma vitamin E and urinary (a; r = 0.
Figure 4: Tissue levels of IPF2α-VI (a) and percent of total aortic lesion areas (b) in apoE–/– mice fed normal chow (Control; n = 8) or chow supplemented with vitamin E (Vitamin E; (n = 11).

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Acknowledgements

We thank P. Smith for technical assistance. This work was supported by grants from the American Heart Association (Grants-in-Aid from the Southeast Pennsylvania Affliate and the National Association), the NIH (HL,AG55323, HL5400 and DK-44730), the NSF for an AMX-360 NMR Instrument (Grant CHE-9013145) and from the W.W. Smith Charitable Trust. G.A.F. is the Robinette Foundation Professor of Cardiovascular Medicine.

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Authors and Affiliations

  1. The Center for Experimental Therapeutics and the Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Domenico Praticò & Garret A. FitzGerald

  2. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Rajendra K. Tangirala, Daniel J. Rader & Garret A. FitzGerald

  3. The Claude Pepper Institute and Department of Chemistry Florida Institute of Technology, Melbourne, 32901, USA

    Joshua Rokach

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  1. Domenico Praticò
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  5. Garret A. FitzGerald
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Correspondence to Garret A. FitzGerald.

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Praticò, D., Tangirala, R., Rader, D. et al. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med 4, 1189–1192 (1998). https://doi.org/10.1038/2685

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