Deletion of p66(shc) gene protects against age-related endothelial dysfunction

Article; Proceedings Paper

关键词: BOVINE CORONARY-ARTERIES;    NITRIC-OXIDE RELEASE;    OXIDATIVE STRESS;    PROSTACYCLIN SYNTHASE;    TYROSINE NITRATION;    PEROXYNITRITE;    SUPEROXIDE;    EXPRESSION;    APOPTOSIS;    INACTIVATION;   

DOI  :  10.1161/01.CIR.0000147731.24444.4D

来源: SCIE

【 摘 要 】

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 p66shc (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.

【 授权许可】

Free