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(Circulation. 2004;110:2889-2895.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

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; 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.).

Correspondence to Francesco Cosentino, MD, PhD, Cardiology & Cardiovascular Research, Institute of Physiology, University of Zürich-Irchel, CH-8057 Zürich, Switzerland. E-mail f_cosentino{at}hotmail.com

Received January 7, 2004; de novo received May 13, 2004; accepted July 14, 2004.

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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