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p66Shc protein, oxidative stress, and cardiovascular complications of diabetes: the missing link

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Abstract

Diabetes affects more than 150 million people worldwide, and it is estimated that this would increase to 299 million by the year 2025. The incidence of and mortality from cardiovascular disease are two- to eightfold higher in subjects with diabetes than in those without, coronary artery disease accounting for the large majority of deaths. Among the full spectrum of biochemical effects of high glucose, generation of oxygen-derived free radicals is one of the main pathophysiological mechanisms linking hyperglycemia to atherosclerosis, nephropathy, and cardiomyopathy. The adaptor protein p66Shc is implicated in mitochondrial reactive oxygen species (ROS) generation and translation of oxidative signals into apoptosis. Indeed, p66Shc−/− mice display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress-induced apoptosis. Accordingly, a series of studies defined the pathophysiological role of p66Shc in cardiovascular disease where ROS represent a substantial triggering component. As p66Shc modulates the production of cellular ROS, it represents a proximal node through which high glucose exerts its deleterious effects on different cell types; indeed, several studies tested the hypothesis that deletion of the p66Shc gene may confer protection against diabetes-related cardiovascular complications. The present review focuses on the reported evidence linking p66Shc signaling pathway to high glucose-associated endothelial dysfunction, atherogenesis, nephropathy, and cardiomyopathy.

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Conflict of interest statement

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Cardiology, 2nd Faculty of Medicine, Sapienza University of Rome, Sant’Andrea Hospital, Via di Grottarossa, 1035-39, 00189, Rome, Italy

    Pietro Francia, Francesco Cosentino, Marzia Schiavoni, Yale Huang, Enrico Perna & Massimo Volpe

  2. I.R.C.C.S. Neuromed, Pozzilli, (IS), Italy

    Massimo Volpe

  3. Cardiology and Cardiovascular Research, University Hospital, Zurich, Switzerland

    Francesco Cosentino, Giovani G. Camici & Thomas F. Lüscher

  4. Institute of Physiology, University of Zurich, Zurich, Switzerland

    Francesco Cosentino, Giovani G. Camici & Thomas F. Lüscher

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  1. Pietro Francia
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  2. Francesco Cosentino
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  3. Marzia Schiavoni
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Correspondence to Massimo Volpe.

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Francia, P., Cosentino, F., Schiavoni, M. et al. p66Shc protein, oxidative stress, and cardiovascular complications of diabetes: the missing link. J Mol Med 87, 885–891 (2009). https://doi.org/10.1007/s00109-009-0499-3

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