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Genetic deletion of p66 Shc adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress
Open accessAbstract
Increased production of reactive oxygen species (ROS) and loss of endothelial NO bioavailability are key features of vascular disease in diabetes mellitus. The p66 Shc adaptor protein controls cellular responses to oxidative stress. Mice lacking p66 Shc (p66 Shc−/− ) 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 Shc−/− mouse. p66 Shc−/− 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 Shc−/− 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, p66 Shc−/− 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 Shc−/− but not in WT mice. We report that p66 Shc−/− mice are resistant to hyperglycemia-induced, ROS-dependent endothelial dysfunction. These data suggest that p66 Shc 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.
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“Additional work has revealed that p66Shc activation is involved in adipogenesis, insulin resistance and cardiovascular complications associated with diabetes mellitus187–189.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [187]
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“Consequently, work has shown that p66Shc−/− mice are protected against streptozotocin-induced diabetic cardiomyopathy191, diabetes mellitus-induced vascular endothelial dysfunction and oxidative stress187.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [187]
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p66Shc mediates SUMO2-induced endothelial dysfunctionPreprint
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p66Shc Mediates SUMO2-induced Endothelial DysfunctionPreprint
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“Consistently, p66Shc deficiency has been shown to protect against age-related endothelial dysfunction [4,5], suggesting a broader role in mitigating oxidative stress-driven aging processes. p66Shc was initially proposed as a gerontogene based on reports that p66Shc knockout (p66Shc − / − ) mice…”
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Metadata
- Authors
- Camici, G. G., Schiavoni, M., Francia, P., Bachschmid, M., Martin-Padura, I., Hersberger, M., Tanner, F. C., Pelicci, P., Volpe, M., Anversa, P., Lüscher, T. F., & Cosentino, F.
- Affiliations
- University of Zurich (CH)
- Sapienza University of Rome (IT)
- University of Konstanz (DE)
- Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy;
- University Hospital Zurich (CH)
- Istituto Neurologico Mediterraneo (IT)
- New York Medical College (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-03-20
- Volume
- 104
- Issue
- 12
- Pages
- 5217-5222
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1829289
- OpenAlex
- W2148034645
- Cited by
- 249
- References
- 39
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 2 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 11 · 2019: 15 · 2018: 14 · 2017: 15 · 2016: 16 · 2015: 14 · 2014: 29 · 2013: 19 · 2012: 20
- FWCI
- 12.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- p66Shc, hyperglycemia, endothelial dysfunction, oxidative stress, reactive oxygen species, diabetes mellitus, streptozotocin-induced diabetes, peroxynitrite, nitrotyrosine, lipid peroxidation, heme oxygenase-1, endothelial nitric oxide synthase, diabetic vascular complications, gene deletion
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Animals, Aorta, Diabetes Mellitus, Experimental, Endothelium, Vascular, Hyperglycemia, Isometric Contraction, Male, Streptozocin, Vasomotor System, Free Radical Scavengers, Gene Deletion, Thiobarbituric Acid Reactive Substances, Oxidative Stress, Peroxynitrous Acid, Adaptor Proteins, Signal Transducing, Luminescence, Mice, Heme Oxygenase-1, Nitric Oxide Synthase Type III, Shc Signaling Adaptor Proteins, In Vitro Techniques
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