O49	Proteomic and metabolomic analysis of atherosclerotic vessels in ApoE-/- mice.
M.Mayr, U.Mayr, Y-L.Chung, X.Yin, J.R.Griffiths, Q.Xu
St Georges, University of London, London, GB.

Background: Proteomics and metabolomics are emerging technologies to study molecular mechanisms of diseases. We demonstrated recently that in combination these techniques have a unique potential to translate proteomic and metabolomic profiles into a functional context (Mayr et al, Circ Res, 2004, 94:e87-96). In the present study, we applied this approach to vessels of apoE-/- mice on normal chow diet. Methods and Results: Using two-dimensional gel electrophoresis and mass spectrometry, we identified about 80 protein species that were dynamically altered during various stages of atherogenesis. Immune activation, redox imbalance and impaired energy metabolism preceded lesion formation in apoE-/- mice. Immunoglobulin deposition occurred prior to the accumulation of other serum proteins, implying an active trapping in the vessel wall. Mass spectrometry data indicated that at least some of the deposited antibodies are directed against phosphocholine. Oxidative stress in the vasculature was reflected by the oxidation status of the redox-sensitive protein 1-Cys peroxiredoxin and correlated to the extent of lesion formation in 12 month-old apoE-/- mice. Nuclear magnetic resonance spectroscopy revealed diminished glucose metabolites and a marked depletion of the adenosine nucleotide and creatine pool in vessels of young apoE-/- mice. Attenuation of lesion formation was associated with alterations of NADPH generating malic enzyme, which provides reducing equivalents for lipid synthesis and glutathione recycling, increased utilisation of glucose and early replenishment of the vascular energy pool, highlighting the intimate connection between oxidative stress and vascular energy metabolism. Conclusion: Our study is the first proteomic and metabolomic analysis of aortas from apoE-/- mice and provides the most comprehensive dataset of protein and metabolite changes during atherogenesis published so far. We demonstrate that attenuated lesion formation is associated with reduced oxidative stress and successful restoration of the vascular energy pool serviced by increased glucose utilization. Importantly, by combining proteomic with metabolomic techniques we can reveal the multiple facets of a single pathogenesis.

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