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. 2003 Feb 18;100(4):2112-6.
doi: 10.1073/pnas.0336359100. Epub 2003 Feb 5.

Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet

Claudio Napoli  1 , Ines Martin-Padura, Filomena de Nigris, Marco Giorgio, Gelsomina Mansueto, Pasquale Somma, Mario Condorelli, Giacomo Sica, Gaetano De Rosa, PierGiuseppe Pelicci
Affiliations

Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet

Claudio Napoli et al. Proc Natl Acad Sci U S A. .

Abstract

Several experimental and clinical studies have shown that oxidized low-density lipoprotein and oxidation-sensitive mechanisms are central in the pathogenesis of vascular dysfunction and atherogenesis. Here, we have used p66(Shc-/-) and WT mice to investigate the effects of high-fat diet on both systemic and tissue oxidative stress and the development of early vascular lesions. To date, the p66(Shc-/-) mouse is the unique genetic model of increased resistance to oxidative stress and prolonged life span in mammals. Computer-assisted image analysis revealed that chronic 21% high-fat treatment increased the aortic cumulative early lesion area by approximately 21% in WT mice and only by 3% in p66(Shc-/-) mice. Early lesions from p66(Shc-/-) mice had less content of macrophage-derived foam cells and apoptotic vascular cells, in comparison to the WT. Furthermore, in p66(Shc-/-) mice, but not WT mice, we found a significant reduction of systemic and tissue oxidative stress (assessed by isoprostanes, plasma low-density lipoprotein oxidizability, and the formation of arterial oxidation-specific epitopes). These results support the concept that p66(Shc-/-) may play a pivotal role in controlling systemic oxidative stress and vascular diseases. Therefore, p66(Shc) might represent a molecular target for therapies against vascular diseases.

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Figures

Figure 1
Figure 1
Computer-assisted image analysis of aortic atherosclerotic lesion areas in p66Shc−/− and WT mice after chronic treatment with 21% HFD. *, P < 0.00001 vs. WT (ND); **, P < 0.05 vs. p66Shc−/− (ND); ***, P < 0.0001 vs. WT (HFD). Results are expressed as the mean ± SEM of lesions from 10 animals in each group.
Figure 2
Figure 2
(A and B) Immunostaining for oxidation-specific epitopes expressed as mAb E06-positive arterial sections: A, p66Shc−/− (HFD); B, WT (HFD). (Magnification, ×320.) Arrows indicate the degree of staining. (C) Graph of cumulative immunostaining results. *, P < 0.0001 vs. WT (ND); **, P = 0.056 (not significant) vs. p66Shc−/− (ND); ***, P < 0.0001 vs. WT (HFD).
Figure 3
Figure 3
TdT-mediated dUTP end labeling (TUNEL)-positive cells in WT (A) and the lower extent in p66Shc−/− (B), both fed on HFD. (Magnification, ×640.) Arrows indicate positive cells.
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