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Genetic deletion of p66(Shc) adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative

Giovanni G Camici1, Marzia Schiavoni, Pietro Francia

  • 1Cardiology and Cardiovascular Research, University Hospital, Zürich, Switzerland.

Proceedings of the National Academy of Sciences of the United States of America
|March 16, 2007
PubMed

Insights

Mice lacking the p66(Shc) adaptor protein resist diabetes-induced vascular damage. These mice show preserved endothelial function and reduced oxidative stress, suggesting p66(Shc) is a target for diabetic complications.

Area of Science:

  • Cardiovascular Biology
  • Metabolic Disease Research
  • Oxidative Stress Mechanisms

Background:

  • Vascular disease in diabetes mellitus is characterized by increased reactive oxygen species (ROS) and reduced endothelial nitric oxide (NO) bioavailability.
  • The p66(Shc) adaptor protein plays a critical role in regulating cellular responses to oxidative stress.
  • Mice deficient in p66(Shc) exhibit enhanced resistance to ROS and extended lifespan.

Purpose of the Study:

  • To investigate the impact of hyperglycemia on endothelial function in p66(Shc) knockout mice, a model of insulin-dependent diabetes mellitus.
  • To determine if the absence of p66(Shc) confers protection against diabetes-induced endothelial dysfunction and oxidative stress.

Main Methods:

  • Induction of diabetes in p66(Shc) knockout (p66(Shc-/-)) and wild-type (WT) mice using streptozotocin injection.
  • Assessment of blood glucose levels, endothelium-dependent relaxations, peroxynitrite generation, nitrotyrosine expression, and lipid peroxidation in aortic tissues.
  • Evaluation of protein expression for antioxidant enzymes, including heme oxygenase 1 and endothelial NO synthase.

Main Results:

  • Diabetic WT mice exhibited significant endothelial dysfunction, increased peroxynitrite (ONOO(-)) generation, nitrotyrosine expression, and lipid peroxidation.
  • In contrast, diabetic p66(Shc-/-) mice did not develop these hyperglycemia-associated abnormalities.
  • Protein levels of heme oxygenase 1 and endothelial NO synthase were upregulated in diabetic p66(Shc-/-) mice but not in WT mice.

Conclusions:

  • Mice lacking p66(Shc) are protected against hyperglycemia-induced, ROS-dependent endothelial dysfunction.
  • The p66(Shc) adaptor protein is implicated in the signaling pathway contributing to vascular damage in hyperglycemia.
  • Targeting the p66(Shc) protein may offer a novel therapeutic strategy for preventing diabetic vascular complications.

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