Online citations, reference lists, and bibliographies.
← Back to Search

Deletion Of P66 Shc 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

Save to my Library
Download PDF
Analyze on Scholarcy Visualize in Litmaps
Share
Reduce the time it takes to create your bibliography by a factor of 10 by using the world’s favourite reference manager
Time to take this seriously.
Get Citationsy
Background— Enhanced production of reactive oxygen species (ROS) has been recognized as the major determinant of age-related endothelial dysfunction. The p66 shc protein controls cellular responses to oxidative stress. Mice lacking p66 shc (p66 shc−/− ) 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 p66 shc−/− 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 (O 2 ) production was determined by coelenterazine-enhanced chemiluminescence. Endothelium-dependent relaxation in response to acetylcholine was age-dependently impaired in WT mice but not in p66 shc−/− mice. Accordingly, an age-related decline of NO release was found in WT but not in p66 shc−/− mice. The expression of eNOS and manganese superoxide dismutase was not affected by aging either in WT or in p66 shc−/− mice, whereas iNOS was upregulated only in old WT mice. It is interesting that old WT mice displayed a significant increase of O 2 production as well as of nitrotyrosine expression compared with young animals. Such age-dependent changes were not found in p66 shc−/− mice. Conclusions— We report that inactivation of the p66 shc gene protects against age-dependent, ROS-mediated endothelial dysfunction. These findings suggest that the p66 shc is part of a signal transduction pathway also relevant to endothelial integrity and may represent a novel target to prevent vascular aging.