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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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Self-citationIntensive Glucose Lowering and Cardiovascular Disease Prevention in Diabetes
Mazzone, T. (2010) · Circulation · doi:10.1161/circulationaha.109.913350 · Cited by 75
Role of oxidative stress in endothelial insulin resistance
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Epigenetic Signatures and Vascular Risk in Type 2 Diabetes: A Clinical Perspective
Paneni, F., Costantino, S., Volpe, M., Lüscher, T. F., & Cosentino, F. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.07.003 · Cited by 70
Self-citationBoosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes
Katare, R., Oikawa, A., Cesselli, D., Beltrami, A. P., Avolio, E., Muthukrishnan, D., Munasinghe, P. E., Angelini, G. D., Emanueli, C., & Madeddu, P. R. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs291 · Cited by 70
The Lifespan-regulator p66Shc in mitochondria: redox enzyme or redox sensor?
Gertz, M., & Steegborn, C. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3147 · Cited by 75
Mitochondria and Oxidative Stress in the Cardiorenal Metabolic Syndrome
Aroor, A. R., Mandavia, C. H., Ren, J. T., Sowers, J. R., & Pulakat, L. (2012) · Cardiorenal Medicine · doi:10.1159/000335675 · Cited by 67
Mitochondrial dysfunction and oxidative stress in diabetic wound
Jiang, G., Jiang, T., Chen, J., Yao, H., Mao, R., Yang, X., Chen, Z., & Li, W. (2023) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.23407 · Cited by 65
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“Moreover, diabetic p66 ko mice do not display impairment of endothelium-dependent relaxations as well as peroxynitrite and nitrotyrosine increase in the aortic tissue and in c-kitþ cardiac progenitor cells.(33,34) An AKT-mediated effect of p66 on eNOS phosphorylation has been observed as well.”
BackgroundResultTorreggiani, M., Liu, H., Wu, J. C., Zheng, F., Cai, W., Striker, G. E., & Vlassara, H. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.090138 · Cited by 62
Structure-functional implications of longevity protein p66Shc in health and disease
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Decreased Superoxide Production in Macrophages of Long-lived p66Shc Knock-out Mice
Tomilov, A. A., Bicocca, V. T., Schoenfeld, R. A., Giorgio, M., Migliaccio, E., Ramsey, J. J., Hagopian, K., Pelicci, P. G., & Cortopassi, G. A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.017491 · Cited by 60
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“Rats with blood glucose levels of 200 mg dl 1 or above [27] and polyuria were considered to be diabetic.”
The role of p66Shcdeletion in age-associated arterial dysfunction and disease states
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Self-citationHistone deacetylases and atherosclerosis
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“…complex in the inner mitochondrial membrane in response to a variety of proapoptotic stimuli and catalyzes the reduction of O2 to H2O2 through an electron transfer from cytochrome c (Camici et al., 2007; Migliaccio et al., 1999; Giorgio et al., Page 13 of 32 Ac ce pt ed M an us cr ip t 2005).”
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Self-citationP66shc and its role in ischemic cardiovascular diseases
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“In later studies, p66Shc−/− mice developed less atherosclerotic plaques, reduced hyperglycemia-dependent endothelial dysfunction as well as decreased damage in a model of hind limb ischemia [3,5–8].”
BackgroundSelf-citationp66Shc protein, oxidative stress, and cardiovascular complications of diabetes: the missing link
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“of acetylcholine-induced vasorelaxation by virtue of an unaltered NO bioavailability [ 5 ].”
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Self-citationMitochondria and Oxidative Stress as a Link between Alzheimer’s Disease and Diabetes Mellitus
Veselov, I. M., Vinogradova, D. V., Maltsev, A. V., Shevtsov, P. N., Spirkova, E. A., Бачурин, С. О., & Shevtsova, E. F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914450 · Cited by 55
“Expression of the p66Shc gene is significantly increased in T2D, and knockout of this gene is able to prevent cognitive impairment in mice with STZ-induced T1D and T2D models; increase resistance to factors associated with aging—oxidative stress, hyperglycemia, hypercholesterolemia, and ischemia [101,102]; prevent end…”
Background
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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