Genetic deletion of p66Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress
Giovanni G. Camici,Marzia Schiavoni,Pietro Francia,Markus Bachschmid,Ines Martin-Padura,Martin Hersberger,Felix C. Tanner,Pier Giuseppe Pelicci,Massimo Volpe,Piero Anversa,Thomas F. Lüscher,Francesco Cosentino +11 more
TLDR
It is reported that p66Shc−/− mice are resistant to hyperglycemia-induced, ROS-dependent endothelial dysfunction and may represent a novel therapeutic target against diabetic vascular complications.Abstract:
Increased production of reactive oxygen species (ROS) and loss of endothelial NO bioavailability are key features of vascular disease in diabetes mellitus. The p66Shc adaptor protein controls cellular responses to oxidative stress. Mice lacking p66Shc (p66Shc−/−) 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 p66Shc−/− mouse. p66Shc−/− 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 p66Shc−/− 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−) generation, nitrotyrosine expression, and lipid peroxidation as measured in the aortic tissue. In contrast, p66Shc−/− 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 p66Shc−/− but not in WT mice. We report that p66Shc−/− mice are resistant to hyperglycemia-induced, ROS-dependent endothelial dysfunction. These data suggest that p66Shc 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.read more
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ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD)
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References
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superoxide production blocks three pathways of hyperglycaemic damage
Takeshi Nishikawa,Diane Edelstein,Xue Liang Du,Sho-ichi Yamagishi,Takeshi Matsumura,Yasufumi Kaneda,Mark A. Yorek,David Beebek,Peter J. Oatesk,Hans-Peter Hammes,Ida Giardino,Michael Brownlee +11 more
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Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage
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TL;DR: This work shows that hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells and is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase.
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The p66shc adaptor protein controls oxidative stress response and life span in mammals
Enrica Migliaccio,Marco Giorgio,Simonetta Mele,Giuliana Pelicci,Paolo Reboldi,Pier Paolo Pandolfi,Luisa Lanfrancone,Pier Giuseppe Pelicci,Pier Giuseppe Pelicci +8 more
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