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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2135.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Proteomic and Metabolomic Analyses of Atherosclerotic Vessels From Apolipoprotein E-Deficient Mice Reveal Alterations in Inflammation, Oxidative Stress, and Energy Metabolism

Manuel Mayr; Yuen-Li Chung; Ursula Mayr; Xiaoke Yin; Lucy Ly; Helen Troy; Salim Fredericks; Yanhua Hu; John R. Griffiths; Qingbo Xu

From the Departments of Cardiac and Vascular Sciences (M.M., U.M., X.Y., L.L., S.F., Y.H., Q.X.) and Basic Medical Sciences (Y.-L.C., H.T., J.R.G.), St George’s, University of London, UK.

Correspondence to Dr Manuel Mayr, Department of Cardiac and Vascular Sciences, St George’s University of London, UK, Cranmer Terrace, London SW17 0RE, UK. E-mail m.mayr{at}sgul.ac.uk

Objective— Proteomics and metabolomics are emerging technologies to study molecular mechanisms of diseases. We applied these techniques to identify protein and metabolite changes in vessels of apolipoprotein E^–/– mice on normal chow diet.

Methods and Results— Using 2-dimensional gel electrophoresis and mass spectrometry, we identified 79 protein species that were altered during various stages of atherogenesis. Immunoglobulin deposition, redox imbalance, and impaired energy metabolism preceded lesion formation in apolipoprotein E^–/– mice. Oxidative stress in the vasculature was reflected by the oxidation status of 1-Cys peroxiredoxin and correlated to the extent of lesion formation in 12-month-old apolipoprotein E^–/– mice. Nuclear magnetic resonance spectroscopy revealed a decline in alanine and a depletion of the adenosine nucleotide pool in vessels of 10-week-old apolipoprotein E^–/– mice. Attenuation of lesion formation was associated with alterations of NADPH generating malic enzyme, which provides reducing equivalents for lipid synthesis and glutathione recycling, and successful replenishment of the vascular energy pool.

Conclusion— Our study provides the most comprehensive dataset of protein and metabolite changes during atherogenesis published so far and highlights potential associations of immune-inflammatory responses, oxidative stress, and energy metabolism.

Our study is a first attempt to show how changes in the proteome and the metabolome are reciprocally connected during atherogenesis and provides evidence that attenuated lesion formation in apolipoprotein E^–/– mice is associated with reduced oxidative stress and successful recovery of the vascular energy pool.

Key Words: animal model • apolipoprotein E • atherosclerosis • metabolomics • oxidative stress • proteomics

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