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.
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.
Napoli
Claudio
C
Department of Medicine, School of Medicine, University of Naples, 80131 Naples, Italy. claunap@tin.it
Martin-Padura
Ines
I
de Nigris
Filomena
F
Giorgio
Marco
M
Mansueto
Gelsomina
G
Somma
Pasquale
P
Condorelli
Mario
M
Sica
Giacomo
G
De Rosa
Gaetano
G
Pelicci
PierGiuseppe
P
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001161:Arteriosclerosis / Q000235:genetics*; D004041:Dietary Fats / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000166:cytology*; D017353:Gene Deletion; D007150:Immunohistochemistry; D008055:Lipids / Q000097:blood; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D011506:Proteins / Q000235:genetics*; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D004041:Dietary Fats; D008055:Lipids; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1