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Deletion of p66 shc Gene Protects Against Age-Related Endothelial Dysfunction
Open accessAbstract
Background— Enhanced production of reactive oxygen species (ROS) has been recognized as the major determinant of age-related endothelial dysfunction. The p66 shc protein controls cellular responses to oxidative stress. Mice lacking p66 shc (p66 shc−/− ) have increased resistance to ROS and a 30% prolonged life span. The present study investigates age-dependent changes of endothelial function in this model. Methods and Results— Aortic rings from young and old p66 shc−/− or wild-type (WT) mice were suspended for isometric tension recording. Nitric oxide (NO) release was measured by a porphyrinic microsensor. Expression of endothelial NO synthase (eNOS), inducible NOS (iNOS), superoxide dismutase, and nitrotyrosine-containing proteins was assessed by Western blotting. Nitrotyrosine residues were also identified by immunohistochemistry. Superoxide (O 2 − ) production was determined by coelenterazine-enhanced chemiluminescence. Endothelium-dependent relaxation in response to acetylcholine was age-dependently impaired in WT mice but not in p66 shc−/− mice. Accordingly, an age-related decline of NO release was found in WT but not in p66 shc−/− mice. The expression of eNOS and manganese superoxide dismutase was not affected by aging either in WT or in p66 shc−/− mice, whereas iNOS was upregulated only in old WT mice. It is interesting that old WT mice displayed a significant increase of O 2 − production as well as of nitrotyrosine expression compared with young animals. Such age-dependent changes were not found in p66 shc−/− mice. Conclusions— We report that inactivation of the p66 shc gene protects against age-dependent, ROS-mediated endothelial dysfunction. These findings suggest that the p66 shc is part of a signal transduction pathway also relevant to endothelial integrity and may represent a novel target to prevent vascular aging.
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“Mutant p66Shc−/− mice have been reported to be resistant to oxidative stress and to have an increased lifespan185, as well as reduced age-dependent endothelial dysfunction186.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [186]
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“recent evidence suggests that mitochondrial dysfunction may play an important role in large elastic artery stiffening and endothelial dysfunction with aging via modulation of oxidative stress (33, 35, 56, 198).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [56]
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The p66Shc Adaptor Protein Controls Oxidative Stress Response in Early Bovine Embryos
Betts, D. H., Bain, N. T., & Madan, P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086978 · Cited by 35
“The ablation of p66Shc has been associated with a wide array of health benefits [39,64,70].”
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
“No effects of p66Shc were detected to any ROS scavenging systems [20–22].”
BackgroundThe Role of Nitric Oxide in Radiation Damage
Ohta, S., Matsuda, S., Gunji, M., et al. (2007) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.30.1102 · Cited by 34
Ginsenoside Rb1 Reverses H2O2-induced Senescence in Human Umbilical Endothelial Cells
Liu, D., Chen, Y., Liu, Y., Hao, B., Zhou, B., Wu, L., Wang, M., Chen, L., Wu, W.-K., & Qian, X. (2011) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e31823c1d34 · Cited by 34
“DISCUSSION Findings in experimental animals(10,11) and observations in humans support the conception that systemic and vascular oxidative stress develops with aging, even in healthy subjects.(12,13) Aging is associated with a marked increase in risk of chronic vascular disease and partly caused by oxidative stress.”
BackgroundEnhanced 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
Ageing and longevity genes in cardiovascular diseases
Liberale, L., Kraler, S. C., Camici, G. G., & Lüscher, T. F. (2020) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13426 · Cited by 34
Cardiovascular protection afforded by caloric restriction: Essential role of nitric oxide synthase
Shinmura, K. (2011) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/j.1447-0594.2010.00675.x · Cited by 31
Aging 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
“Male C57BL/6 mice from the following age groups were examined: (1) young group, aged 11 weeks; (2) intermediate group, aged 62 weeks; and (3) old group, aged 105 weeks.”
MethodYan, X., Liang, F., Li, D., & Zheng, J. (2014) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-014-2208-y · Cited by 31
Anti-Aging Medicine: Molecular Basis for Endothelial Cell-Targeted Strategies – A Mini-Review
Camici, G. G., Shi, Y., Cosentino, F., Francia, P., & Lüscher, T. F. (2010) · Gerontology · doi:10.1159/000314227 · Cited by 31
Self-citationRios, F. J. O., Ciuceis, C. D., Georgiopoulos, G. A., Lazaridis, A. A., Nosalski, R., Pavlidis, G., Tual‐Chalot, S., Rosei, C. A., Camargo, L. L., Dąbrowska, E., et al. (2024) · Hypertension · doi:10.1161/hypertensionaha.123.22483 · Cited by 34
“101 SHRSP exhibit increased p66Shc by mechanisms dependent on mineralocordicoid receptor-Nox1 activation axis 115 and p66Shc deficient mice exhibit reduction in blood pressure induced by Ang-II 116 and vascular dysfunction in obesity 100 and stroke.”
BackgroundThe Endothelium Abridges Insulin Resistance to Premature Aging
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
Paneni, F., Costantino, S., Kränkel, N., Cosentino, F., & Lüscher, T. F. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw073 · Cited by 31
Self-citationFetoni, A. R., Eramo, S. L. M., Paciello, F., Rolesi, R., Samengo, D., Paludetti, G., Troiani, D., & Pani, G. (2016) · Scientific Reports · doi:10.1038/srep25450 · Cited by 28
DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature
Shah, A. V., & Bennett, M. R. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.03.050 · Cited by 27
Lüscher, T. F., & Steffel, J. (2008) · Circulation Research · doi:10.1161/01.res.0000303937.73170.31 · Cited by 29
Huang, T., Chen, C.-C., Liu, H.-M., Lee, T.-Y., & Shieh, S.-H. (2017) · Scientific Reports · doi:10.1038/s41598-017-02881-z · Cited by 27
p66Shc 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
Cell senescence: basic mechanisms and the need for computational networks in vascular ageing
Regnault, V., Challande, P., Pinet, F., Li, Z., & Lacolley, P. J. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa318 · Cited by 27
Targeting senescent cells for vascular aging and related diseases
Ding, Y.-N., Wang, H.-Y., Chen, H., & Liu, D. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.08.009 · Cited by 30
Donato, A. J., Eskurza, I., Jablonski, K., Gano, L. B., Pierce, G. L., & Seals, D. R. (2008) · Journal of Applied Physiology · doi:10.1152/japplphysiol.90629.2008 · Cited by 27
D'Agostino, M., Torcinaro, A., Madaro, L., Marchetti, L., Sileno, S., Beji, S., Salis, C., Proietti, D., Imeneo, G., Capogrossi, M. C., et al. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/4814696 · Cited by 26
“Since ROS rapidly react with NO, generating nitrogen species, such as peroxynitrite [33], it is conceivable that p66Shc deletion enhances nitric oxide bioavailability [34], thus, favoring myogenic differentiation.”
BackgroundDo we age because we have mitochondria?
Bereiter‐Hahn, J. (2013) · PROTOPLASMA · doi:10.1007/s00709-013-0515-x · Cited by 25
Berry, 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).”
BackgroundSelf-citationZawada, A. M., Rogacev, K. S., & Heine, G. H. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft042 · Cited by 25
“In murine studies, p66Shc deletion renders resistance to oxidative stress, thus prolonging life span and protecting against age-related endothelial dysfunction [56, 57].”
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
Vascular ageing in hypertension: Focus on mitochondria
Forte, M., Stanzione, R., Cotugno, M., Bianchi, F., Marchitti, S., & Rubattu, S. D. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111267 · Cited by 26
Novel Insights into the PKCβ-dependent Regulation of the Oxidoreductase p66Shc
Haller, M., Khalid, S., Kremser, L., Fresser, F., Furlan, T., Hermann, M., Guenther, J., Drasche, A., Leitges, M., Giorgio, M., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.752766 · Cited by 24
Pérez, H., Finocchietto, P. V., Alippe, Y., Rebagliati, I., Elguero, M. E., Villalba, N., Poderoso, J. J., & Carreras, M. C. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/8561892 · Cited by 23
p66 Shc as the Engine of Vascular Aging
Paneni, F., & Cosentino, F. (2012) · Current Vascular Pharmacology · doi:10.2174/157016112803520747 · Cited by 23
Self-citationChou, S.-H., Lee, Y.-C., Huang, C.-F., Wang, Y., Yu, H., & Lau, Y. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq095 · Cited by 23
Physical activity may drive healthy microvascular ageing via downregulation of p66Shc
Streese, L., Khan, A. W., Deiseroth, A., Hussain, S., Suades, R., Tiaden, A., Kyburz, D., Hanssen, H., & Cosentino, F. (2020) · European Journal of Preventive Cardiology · doi:10.1177/2047487319880367 · Cited by 21
“The mitochondrial adaptor p66 plays a key role in ageing-induced oxidative stress.(9) We have also reported a significant upregulation of p66 in peripheral blood mononuclear cells isolated from patients with type 2 diabetes.”
BackgroundSelf-citationSmoking p66Shc Knocked Out Mice Develop Respiratory Bronchiolitis with Fibrosis but Not Emphysema
Lunghi, B., Cunto, G. D., Cavarra, E., Fineschi, S., Bartalesi, B., Lungarella, G., & Lucattelli, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119797 · Cited by 22
“Consistently, p66 mice show reduced levels of systemic (isoprostane) and tissue (nitrotyrosines, 8-oxo-dG) oxidative stress markers [12, 14, 18, 19] and enhanced resistance to oxidative stress induced by carbon tetrachloride [20], ethanol [21], hypercholesterolemia (atherogenesis) [18], acute ischemia [22], and angiot…”
BackgroundGuntani, A., Matsumoto, T., Kyuragi, R., Iwasa, K., Onohara, T., Itoh, H., Katušić, Z. S., & Maehara, Y. (2011) · Journal of Surgical Research · doi:10.1016/j.jss.2011.03.024 · Cited by 22
The Role of Oxidative Stress in Endothelial Dysfunction and Vascular Inflammation
Osto, E., & Cosentino, F. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-373866-0.00022-8 · Cited by 23
Self-citation
Metadata
- Authors
- Francia, P., delli Gatti, C., Bachschmid, M., Martin-Padura, I., Savoia, C., Migliaccio, E., Pelicci, P. G., Schiavoni, M., Lüscher, T. F., Volpe, M., & Cosentino, F.
- Affiliations
- University of Konstanz (DE)
- From Cardiovascular Research & Cardiology, Institute of Physiology, Zürich, Irchel and University Hospital, Zürich, Switzerland (P.F., C.D.G., M.S., T.F.L., F.C.); Division of Cardiology, 2nd Faculty of Medicine, University “La Sapienza,” Rome, and IRCCS Neuromed, Pozzilli (IS), Italy (P.F., C.S., M.V., F.C.); Department of Biology, University of Konstanz, Germany (M.B.); and Department of Experimental Oncology of the European Institute of Oncology, Milan, Italy (I.M.-P., E.M., P.G.P.).
- ORCID
- Venue
- Circulation
- Published
- 2004-11-02
- Volume
- 110
- Issue
- 18
- Pages
- 2889-2895
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2101209889
- Semantic Scholar
- 3f117729d32b45e441d1ca919d8085736409dd05
- Cited by
- 298
- References
- 29
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 6 · 2023: 6 · 2022: 9 · 2021: 13 · 2020: 15 · 2019: 13 · 2018: 14 · 2017: 11 · 2016: 14 · 2015: 10 · 2014: 17 · 2013: 20 · 2012: 18
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Update notices
- correction (2005-01-25)
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Circulation (publishedVersion, public-domain)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Research Foundation
- Schweizerische Herzstiftung
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- p66Shc, endothelial dysfunction, vascular aging, reactive oxygen species, oxidative stress, nitric oxide, nitrotyrosine, superoxide production, endothelial nitric oxide synthase, inducible nitric oxide synthase, superoxide dismutase, acetylcholine-induced relaxation, knockout mice
- MeSH terms
- Src Homology 2 Domain-Containing, Transforming Protein 1, Aging, Animals, Aorta, Endothelium, Vascular, Isometric Contraction, Longevity, Male, Nitric Oxide, Proteins, Superoxide Dismutase, Tyrosine, Vasoconstriction, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Nitric Oxide Synthase, Adaptor Proteins, Signal Transducing, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Shc Signaling Adaptor Proteins
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