Published Online
on October 25, 2004

A more recent version of this article appeared on November 2, 2004

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Submitted on January 7, 2004
Revised on May 13, 2004
Accepted on July 14, 2004

Deletion of p66^shc Gene Protects Against Age-Related Endothelial Dysfunction

Pietro Francia MD, Chiara delli Gatti MD, Markus Bachschmid PhD, Ines Martin-Padura PhD, Carmine Savoia MD, Enrica Migliaccio MD, Pier Giuseppe Pelicci MD, Marzia Schiavoni MD, Thomas Felix Lüscher MD, Massimo Volpe MD, and Francesco Cosentino MD, PhD^*

From Cardiovascular Research & Cardiology, Institute of Physiology, Zürich, Irchel and University Hospital, Zürich, Switzerland (P.F., C.D.G., M.S., T.F.L., F.C.); Division of Cardiology, 2nd Faculty of Medicine, University "La Sapienza," Rome, and IRCCS Neuromed, Pozzilli (IS), Italy (P.F., C.S., M.V., F.C.); Department of Biology, University of Konstanz, Germany (M.B.); and Department of Experimental Oncology of the European Institute of Oncology, Milan, Italy (I.M.-P., E.M., P.G.P.).

^* To whom correspondence should be addressed. E-mail: f_cosentino{at}hotmail.com.

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 (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 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 O₂^- 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.

Key words: aging • endothelium • free radicals • nitric oxide • genes

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