Genetic deletion of p66 <sup>Shc</sup> adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress

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  • Massimo Volpe
    Division of Cardiology, Second Faculty of Medicine, University La Sapienza, 00189 Rome, Italy;
  • PierGiuseppe Pelicci
    Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy;
  • Piero Anversa
    **New York Medical College, Cardiovascular Research Institute, Valhalla, NY 10595; and
  • Thomas F. Lüscher
    *Cardiology and Cardiovascular Research, University Hospital, Zürich, Institute of Physiology, University of Zürich, CH-8057 Zürich, Switzerland;
  • Francesco Cosentino
    *Cardiology and Cardiovascular Research, University Hospital, Zürich, Institute of Physiology, University of Zürich, CH-8057 Zürich, Switzerland;
  • Markus Bachschmid
    Department of Biology, University of Konstanz, D-78457 Konstanz, Germany;
  • Marzia Schiavoni
    *Cardiology and Cardiovascular Research, University Hospital, Zürich, Institute of Physiology, University of Zürich, CH-8057 Zürich, Switzerland;
  • Pietro Francia
    Division of Cardiology, Second Faculty of Medicine, University La Sapienza, 00189 Rome, Italy;
  • Giovanni G. Camici
    *Cardiology and Cardiovascular Research, University Hospital, Zürich, Institute of Physiology, University of Zürich, CH-8057 Zürich, Switzerland;
  • Ines Martin-Padura
    Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy;
  • Martin Hersberger
    Institute of Clinical Chemistry, University Hospital, CH-8057 Zürich, Switzerland;
  • Felix C. Tanner
    *Cardiology and Cardiovascular Research, University Hospital, Zürich, Institute of Physiology, University of Zürich, CH-8057 Zürich, Switzerland;
  • University of Zurich
  • Cosentino, Francesco

書誌事項

公開日
2007-03-20
DOI
  • 10.1073/pnas.0609656104
公開者
Proceedings of the National Academy of Sciences

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説明

<jats:p> Increased production of reactive oxygen species (ROS) and loss of endothelial NO bioavailability are key features of vascular disease in diabetes mellitus. The p66 <jats:sup>Shc</jats:sup> adaptor protein controls cellular responses to oxidative stress. Mice lacking p66 <jats:sup>Shc</jats:sup> (p66 <jats:sup>Shc−/−</jats:sup> ) have increased resistance to ROS and prolonged life span. The present work was designed to investigate hyperglycemia-associated changes in endothelial function in a model of insulin-dependent diabetes mellitus p66 <jats:sup>Shc−/−</jats:sup> mouse. p66 <jats:sup>Shc−/−</jats:sup> and wild-type (WT) mice were injected with citrate buffer (control) or made diabetic by an i.p. injection of 200 mg of streptozotocin per kg of body weight. Streptozotocin-treated p66 <jats:sup>Shc−/−</jats:sup> and WT mice showed a similar increase in blood glucose. However, significant differences arose with respect to endothelial dysfunction and oxidative stress. WT diabetic mice displayed marked impairment of endothelium-dependent relaxations, increased peroxynitrite (ONOO <jats:sup>−</jats:sup> ) generation, nitrotyrosine expression, and lipid peroxidation as measured in the aortic tissue. In contrast, p66 <jats:sup>Shc−/−</jats:sup> diabetic mice did not develop these high-glucose-mediated abnormalities. Furthermore, protein expression of the antioxidant enzyme heme oxygenase 1 and endothelial NO synthase were up-regulated in p66 <jats:sup>Shc−/−</jats:sup> but not in WT mice. We report that p66 <jats:sup>Shc−/−</jats:sup> mice are resistant to hyperglycemia-induced, ROS-dependent endothelial dysfunction. These data suggest that p66 <jats:sup>Shc</jats:sup> adaptor protein is part of a signal transduction pathway relevant to hyperglycemia vascular damage and, hence, may represent a novel therapeutic target against diabetic vascular complications. </jats:p>

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