TY - JOUR
T1 - Deletion of p66shc gene protects against age-related endothelial dysfunction
AU - Francia, Pietro
AU - Delli Gatti, Chiara
AU - Bachschmid, Markus
AU - Martin-Padura, Ines
AU - Savoia, Carmine
AU - Migliaccio, Enrica
AU - Pelicci, Pier Giuseppe
AU - Schiavoni, Marzia
AU - Lüscher, Thomas Felix
AU - Volpe, Massimo
AU - Cosentino, Francesco
PY - 2004/11/2
Y1 - 2004/11/2
N2 - 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.
AB - 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.
KW - Aging
KW - Endothelium
KW - Free radicals
KW - Genes
KW - Nitric oxide
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U2 - 10.1161/01.CIR.0000147731.24444.4D
DO - 10.1161/01.CIR.0000147731.24444.4D
M3 - Article
C2 - 15505103
AN - SCOPUS:8144229685
VL - 110
SP - 2889
EP - 2895
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 18
ER -