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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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“Genetic models of p66Shc mice are characterised by an increased resistance to oxidative stress, longevity and reduced atherosclerosis under a high fat diet (14, 15).”
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Self-citationReactive Oxygen Species in Diabetes-induced Vascular Damage, Stroke, and Alzheimer's Disease
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“Endothelial dysfunction in a mouse model of diabetes is modified by p66 [26].”
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Self-citationSpecific PKC βII inhibitor: one stone two birds in the treatment of diabetic foot ulcers
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RetractedCardiovascular determinants of life span
Shi, Y., Camici, G. G., & Lüscher, T. F. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0727-2 · Cited by 41
“Nevertheless, p66Shc knockout mice are protected from diabetes-induced endothelial dysfunction [19] and diabetic glomerulopathy [65], which is due to reduced production of ROS and a decreased cellular apoptosis (Fig. 3). The above-described data underscore the pivotal role of p66Shc in diabetes-induced ROS production…”
BackgroundInfluentialSelf-citationPositive and negative regulation of antigen receptor signaling by the Shc family of protein adapters
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“Given that p66Shc gene expression and F2-IsoP levels were increased in blood monocytes from diabetic patients (Camici et al., 2007), this suggests that these two molecules may also be clinical markers of stress in other disorders involving glucose and redox dysregulation including stroke and transient ischemic attack.”
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P66Shc-SIRT1 Regulation of Oxidative Stress Protects Against Cardio-cerebral Vascular Disease
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P66Shc and vascular endothelial function
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“Subsequently, Camici et al. (2007) [50] reported that diabetes increases the expression of p66Shc in the vasculature and p66Shc knockout mice are protected against diabetes-induced vascular endothelial dysfunction and oxidative stress.”
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p66Shc in Cardiovascular Pathology
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“Additionally, the p66Shc adaptor protein has been shown to participate in mitochondrial ROS production, by serving as a redox-sensitive enzyme that oxidizes cytochrome c, in response to high glucose concentration (Camici et al., 2007; Cosentino et al., 2008).”
BackgroundProoxidant Properties of p66shc Are Mediated by Mitochondria in Human Cells
Galimov, E. R., Chernyak, B. V., Sidorenko, A. S., Tereshkova, A. V., & Chumakov, P. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086521 · Cited by 34
Molecular mechanisms of vascular dysfunction and cardiovascular biomarkers in type 2 diabetes.
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Self-citationEnhanced age-dependent cerebrovascular dysfunction is mediated by adaptor protein p66Shc
Shi, Y., Savarese, G., Filardi, P. P., Lüscher, T. F., & Camici, G. G. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.06.025 · Cited by 33
Self-citationAging Induces Endothelial Dysfunction While Sparing Arterial Thrombosis
Stämpfli, S. F., Akhmedov, A. T., Gebhard, C., Lohmann, C., Holy, E. W., Rozenberg, I., Spescha, R. D., Shi, Y., Lüscher, T. F., Tanner, F. C., et al. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.110.206920 · Cited by 32
Self-citationAnti-Aging Medicine: Molecular Basis for Endothelial Cell-Targeted Strategies – A Mini-Review
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“In line with the above, p66 Shc protein expression is increased in aortas of type I diabetes mice [”
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Avogaro, A., de Kreutzenberg, S. V., Federici, M., & Fadini, G. P. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.113.000262 · Cited by 30
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“Finally, it has been reported that the increased production of free radicals observed in diabetes, a major risk factor for cardiovascular disease, results from reduced activity of superoxide dismutase [48, 49] , reduced expression of heme oxygenase [48] , as well as from enhanced expression of NAD(P)H oxidase [50] and…”
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“Several groups have shown that p66 inhibition confers protection against oxidative stress in various experimental contexts and disease models (Migliaccio et al., 1999; Camici et al., 2007).”
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“This finding is consistent with that found during last years and confirmed in a recent work [29,30] which showed an increase of nitrotyrosine levels in the aortas of diabetic wild type mice as compared to control wild type mice.”
Resultp66Shc Signaling Mediates Diabetes-Related Cognitive Decline
Minami, Y., Sonoda, N., Hayashida, E., Makimura, H., Ide, M., Ikeda, N., Ohgidani, M., Kato, T. A., Seki, Y., Maeda, Y., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-21426-6 · Cited by 27
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Hyperglycemia-Induced Endothelial Dysfunction
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Therapeutic Interventions to Block Oxidative Stress-Associated Pathologies
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The p66Shc Redox Protein and the Emerging Complications of Diabetes
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“In fact, after streptozotocin injection, both p66 Shc-/- and wild-type mice showed the same increase in blood glucose levels [51,52].”
BackgroundBerry, A., Amrein, I., Nötzli, S., Lazic, S. E., Bellisario, V., Giorgio, M., Pelicci, P. G., Alleva, E., Lipp, H., & Cirulli, F. (2012) · Hippocampus · doi:10.1002/hipo.22042 · Cited by 24
“One of the characteristics of the p66 Shc knock out is a vascular resistance against OS (Napoli et al., 2003; Camici et al., 2007), an effect that is particularly apparent while aging (Francia et al., 2004).”
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“Of note, high glucose condition can generate oxidative stress in living body and induce cell injury, including the participation of free radicals [41, 42] and the breakdown of antioxidase system [43].”
BackgroundmiR-412-5p targets Xpo1 to regulate angiogenesis in hemorrhoid tissue
Wang, C., Lü, H., Luo, C., Song, C., Wang, Q., Peng, Y., Xin, Y., Liu, T., & Yang, W. (2019) · Gene · doi:10.1016/j.gene.2019.04.058 · Cited by 24
PITX2 Enhances the Regenerative Potential of Dystrophic Skeletal Muscle Stem Cells
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“Western blot analyses were performed as described previously (Camici et al., 2007).”
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A Mitochondrial Approach to Cardiovascular Risk and Disease
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p66 Shc as the Engine of Vascular Aging
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Self-citationThe Role of p66Shc in Diabetes: A Comprehensive Review from Bench to Bedside
Mousavi, S., Tabari, M. A. K., Bagheri, A., Samieefar, N., Shaterian, N., & Kelishadi, R. (2022) · Journal of Diabetes Research · doi:10.1155/2022/7703520 · Cited by 22
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RetractedThe Role of Oxidative Stress in Endothelial Dysfunction and Vascular Inflammation
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“Recently, genetic deletion of p66shc has been found to prevent the hyperglycemia-induced endothelial dysfunction and oxidative stress [11].”
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“The deletion of p66shc protects against age-associated endothelial dysfunction [4] and prevents hyperglycemia-induced endothelial dysfunction [5].”
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Shc depletion stimulates brown fat activity in vivo and in vitro
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“…aging (Migliaccio et al., 1999) over 15 years ago, and they are lean, insulin sensitive, glucose tolerant (Berniakovich et al., 2008; Ranieri et al., 2010; Tomilov et al., 2011), and stress-resistant (Napoli et al., 2003; Camici et al., 2007; Menini et al., 2007; Martin-Padura et al., 2008).”
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“Studies involving p66SHC-knock out mice have been shown to be resistant to oxidative stress and cardiovascular pathologies, such as atherosclerosis and endothelial disorders [99,100].”
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Epigenetic enhancement of p66Shc during cellular replicative or premature senescence
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“Recently, genetic deletion of p66shc has been found to prevent oxidative stress (Camici et al., 2007).”
BackgroundFavre, J., Yıldırım, C., Leyen, T. A., Chen, W. J. Y., van Genugten, R. E., van Golen, L. W., García-Vallejo, J. J., Musters, R. J. P., Baggen, J. M. C., Fontijn, R. D., et al. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.08.003 · Cited by 15
Reactive Oxygen Species: Friends and Foes of Signal Transduction
Retta, S. F., Chiarugi, P., Trabalzini, L., Pinton, P., & Belkin, A. M. (2012) · Journal of Signal Transduction · doi:10.1155/2012/534029 · Cited by 16
Borkowska, A., Popowska, U., Spodnik, J. H., Herman-Antosiewicz, A., Woźniak, M., & Antosiewicz, J. (2020) · Nutrients · doi:10.3390/nu12030668 · Cited by 15
Salhan, D., Pathak, S., Husain, M., Tandon, P., Kumar, D., Malhotra, A., Meggs, L. G., & Singhal, P. C. (2011) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00024.2011 · Cited by 14
RetractedA complex of Shc and Ran-GTPase localises to the cell nucleus
George, R., Chan, H., Ahmed, Z., Suen, K. M., Stevens, C. N., Levitt, J. A., Suhling, K., Timms, J. F., & Ladbury, J. E. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-8667-8 · Cited by 14
Epigenetic modulation of vascular diseases: Assessing the evidence and exploring the opportunities
Schiattarella, G. G., Madonna, R., Linthout, S. V., Thum, T., Schulz, R., Ferdinándy, P., & Perrino, C. (2018) · Vascular Pharmacology · doi:10.1016/j.vph.2018.02.009 · Cited by 14
Mitochondria at the heart of cardiovascular protection: p66shc—friend or foe?
Heusch, G. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu409 · Cited by 14
P66Shc expression in diabetic rat retina
Zhao, M., Hu, J., Li, S., Wu, Q. E., & Lu, P. (2018) · BMC Ophthalmology · doi:10.1186/s12886-018-0724-3 · Cited by 13
“Genetic deletion of p66Shc attenuated hyperglycaemiainduced endothelial dysfunction and oxidative damage [24, 25].”
BackgroundAdapter proteins regulate insulin resistance and lipid metabolism in obesity
Chen, Z. (2016) · 中国科学通报：英文版 · doi:10.1007/s11434-016-1058-2 · Cited by 13
Vashistha, H., Singhal, P. C., Malhotra, A., Husain, M., Mathieson, P. W., Saleem, M. A., Kuriakose, C., Seshan, S. V., Wilk, A. M., Valle, L. D., et al. (2012) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00246.2012 · Cited by 13
Self-citationRole of p66shc in skeletal muscle function
Granatiero, V., Gherardi, G., Vianello, M., Salerno, E., Zecchini, E., Toniolo, L., Pallafacchina, G., Murgia, M., Blaauw, B., Rizzuto, R., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-06363-0 · Cited by 14
Chamgordani, M. K., Bardestani, A., Ebrahimpour, S., & Esmaeili, A. (2023) · BMC Pharmacology and Toxicology · doi:10.1186/s40360-023-00725-3 · Cited by 12
Application and progress of 3D printed biomaterials in osteoporosis
Wang, C., Liu, A., Zhao, Z., Ying, T., Deng, S. H., Jian, Z., Zhang, X., Yi, C., & Li, D. (2025) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2025.1541746 · Cited by 12
The effect of p66shc protein on the resistance of the RKO colon cancer cell line to oxidative stress
Galimov, E. R., Sidorenko, A. S., Tereshkova, A. V., Pletyushkina, O. Y., Chernyak, B. V., & Chumakov, P. M. (2012) · Molecular Biology · doi:10.1134/s0026893312010062 · Cited by 12
“Nevertheless, these results were not replicated in mouse embryonic fibroblast lines as well as in animal models [3, 19–21], and therefore it could be hypothesized that p66shc dependent signaling pathways somehow differ in normal and transformed cells and/or there are some kinds of differences between human and mice ce…”
ResultTzschoppe, A., Doerr, H. G., Rascher, W., Goecke, T. W., Beckmann, M. W., Schild, R. L., Struwe, E., Geisel, J., Jung, H., & Dötsch, J. (2013) · Prenatal Diagnosis · doi:10.1002/pd.4096 · Cited by 11
Das, S. K., Yuan, Y. F., & Li, M. Q. (2017) · Cellular Reprogramming · doi:10.1089/cell.2016.0050 · Cited by 11
“…p66Shc over-expression not only results in ROS-induced apoptosis of EPC but also decreases EPC motility by down-regulating the antioxidant enzyme and/or or deregulating VEGF, thereby eventually decreasing NO bioavailability (Camici et al., 2007; de Kreutzenberg et al., 2010; Zhou et al., 2011).”
Linking diabetes and atherosclerosis
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Cosentino, F., Grant, P. J., Aboyans, V., Bailey, C. J., Ceriello, A., Delgado, V., Federici, M., Filippatos, G., Grobbee, D. E., Hansen, T. B., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz486 · Cited by 4,763
Self-citationThe Impact of Glycaemic Variability on Vascular Dysfunction in Diabetes
Offler, L. J., Wells, L. K., & Palmer, T. M. (2025) · Biomolecules · doi:10.3390/biom15111544 · Cited by 12
“Ser36 phosphorylation of the mitochondrial p66 Shc protein [67] is thought to increase oxidative damage and mitochondrial apoptosis [68,69].”
Promise of endothelial progenitor cell for treatment of diabetic retinopathy
Bhatwadekar, A. D., Shaw, L. C., & Grant, M. B. (2010) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.09.75 · Cited by 9
Zanetti, M., Barazzoni, R., Cappellari, G. G., Burekovic, I., Bosutti, A., Stocca, A., Bianco, F., Ianche, M., Panzetta, G. O., & Guarnieri, G. (2011) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2010.12.006 · Cited by 8
Rattanavich, R., Plagov, A., Kumar, D., Rai, P., Lederman, R., Salhan, D., Vashistha, H., Malhotra, A., Meggs, L. G., & Singhal, P. C. (2013) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2013.03.001 · Cited by 8
Mitochondrial Translocation of P66Shc Aggravates Cisplatin-induced AKI by Promoting Ferroptosis
Yang, M., Liu, Y., Han, Y., Zhang, W., Zhang, H., & Yang, S. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220819112808 · Cited by 8
Recent advances of adapter proteins in the regulation of heart diseases
Li, T., Jia, L., Li, Y., Song, C., & Chen, Z. (2016) · Heart Failure Reviews · doi:10.1007/s10741-016-9582-3 · Cited by 6
Lee, S. K., Lee, J. Y., Joo, H. K., Cho, E., Kim, C., Lee, S. D., Park, J. B., & Jeon, B. H. (2012) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2012.16.3.199 · Cited by 7
“Genetic deletion of p66shc prevents endothelial dysfunction [8,9].”
BackgroundFu, G., Chen, A. F., Xu, Q., Han, B., Huang, G.-Z., & Zhong, Y. (2017) · Free Radical Research · doi:10.1080/10715762.2017.1393665 · Cited by 7
Dong, W., Zhang, C., Zhao, S., Li, Q., Kang, L., Guo, L., Lei, X., & Zhai, X. (2016) · Drug Design Development and Therapy · doi:10.2147/dddt.s84820 · Cited by 7
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How Can Molecules Induce Hemorrhoids? The Role of Genetics and Epigenetics in Hemorrhoidal Disease
Parol, B., Sas, O., Mazurek, M., Data, K., Woźniak, S., & Domagała, Z. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199394 · Cited by 8
“The p66 SHC has a role in the Ras signaling pathway [89,90,92,93], inducing apoptosis and aging [89–91 , 94–”
Albiero, M., D’Anna, M., Bonora, B. M., Zuccolotto, G., Rosato, A., Giorgio, M., Iori, E., Avogaro, A., & Fadini, G. P. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0097 · Cited by 6
“…is also linked to hyperglycemic memory, through which high glucose induces epigenetic fingerprints, such as increased histone-3 acetylation and decreased promoter methylation, lasting beyond restoration of euglycemia, and developing a vicious cycle of p66Shc activation and oxidative damage (10, 48).”
Diabetes Mellitus and Metabolic Syndrome
Cosentino, F., Rydén, L., Francia, P., & Mellbin, L. (2009) · doi:10.1093/med/9780199566990.003.014 · Cited by 6
Self-citation
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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