Deletion of p66shc gene protects against age-related endothelial dysfunction

Pietro Francia, Chiara Delli Gatti, Markus Bachschmid, Ines Martin-Padura, Carmine Savoia, Enrica Migliaccio, Pier Giuseppe Pelicci, Marzia Schiavoni, Thomas Felix Lüscher, Massimo Volpe, Francesco Cosentino

Research output: Contribution to journalArticlepeer-review

Abstract

Background - Enhanced production of reactive oxygen species (ROS) has been recognized as the major determinant of age-related endothelial dysfunction. The p66shc protein controls cellular responses to oxidative stress. Mice lacking p66shc (p66shc-/-) have increased resistance to ROS and a 30% prolonged life span. The present study investigates age-dependent changes of endothelial function in this model. Methods and Results - Aortic rings from young and old p66shc-/- or wild-type (WT) mice were suspended for isometric tension recording. Nitric oxide (NO) release was measured by a porphyrinic microsensor. Expression of endothelial NO synthase (eNOS), inducible NOS (iNOS), superoxide dismutase, and nitrotyrosine-containing proteins was assessed by Western blotting. Nitrotyrosine residues were also identified by immunohistochemistry. Superoxide (O2 -) production was determined by coelenterazine-enhanced chemiluminescence. Endothelium-dependent relaxation in response to acetylcholine was age-dependently impaired in WT mice but not in p66shc-/- mice. Accordingly, an age-related decline of NO release was found in WT but not in p66shc-/- mice. The expression of eNOS and manganese superoxide dismutase was not affected by aging either in WT or in p66shc-/- mice, whereas iNOS was upregulated only in old WT mice. It is interesting that old WT mice displayed a significant increase of O2 - production as well as of nitrotyrosine expression compared with young animals. Such age-dependent changes were not found in p66shc-/- mice. Conclusions - We report that inactivation of the p66shc gene protects against age-dependent, ROS-mediated endothelial dysfunction. These findings suggest that the p66shc is part of a signal transduction pathway also relevant to endothelial integrity and may represent a novel target to prevent vascular aging.

Original languageEnglish
Pages (from-to)2889-2895
Number of pages7
JournalCirculation
Volume110
Issue number18
DOIs
Publication statusPublished - Nov 2 2004

Keywords

  • Aging
  • Endothelium
  • Free radicals
  • Genes
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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