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, Ines Martin-Padura, Filomena De Nigris, Marco Giorgio, Gelsomina Mansueto, Pasquale Somma, Mario Condorelli, Giacomo Sica, Gaetano De Rosa, PierGiuseppe G. Pelicci

Research output: Contribution to journalArticlepeer-review

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 p66Shc-/- 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 p66Shc-/- 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 ≈21% in WT mice and only by 3% in p66Shc-/- mice. Early lesions from p66Shc-/- mice had less content of macrophage-derived foam cells and apoptotic vascular cells, in comparison to the WT. Furthermore, in p66Shc-/- 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 p66Shc-/- may play a pivotal role in controlling systemic oxidative stress and vascular diseases. Therefore, p66Shc might represent a molecular target for therapies against vascular diseases.

Original languageEnglish
Pages (from-to)2112-2116
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number4
DOIs
Publication statusPublished - Feb 18 2003

Keywords

  • Atherosclerosis
  • Oxygen radicals
  • Transgenic mouse

ASJC Scopus subject areas

  • Genetics
  • General

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