1. 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.
- Author
-
Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P, Condorelli M, Sica G, De Rosa G, and Pelicci P
- Subjects
- Animals, Immunohistochemistry, Lipids blood, Male, Mice, Mice, Knockout, Shc Signaling Adaptor Proteins, Src Homology 2 Domain-Containing, Transforming Protein 1, Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Apoptosis genetics, Arteriosclerosis genetics, Dietary Fats administration & dosage, Endothelium, Vascular cytology, Gene Deletion, Longevity genetics, Oxidative Stress, Proteins genetics
- 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.
- Published
- 2003
- Full Text
- View/download PDF