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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
p66Shc−/− mice have reduced age-dependent endothelial dysfunction.
“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]
Mitochondrial dysfunction may play an important role in large elastic artery stiffening and endothelial dysfunction with aging via modulation of oxidative stress.
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Oxidants, oxidative stress and the biology of ageing
Finkel, T., & Holbrook, N. J. (2000) · Nature · doi:10.1038/35041687 · Cited by 9,413 · see citing works
Aging: a theory based on free radical and radiation chemistry
Harman, D. (1956) · Journal of Gerontology · doi:10.1093/geronj/11.3.298 · Cited by 8,567 · see citing works
Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly
Beckman, J. S., & Koppenol, W. H. (1996) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1996.271.5.c1424 · Cited by 5,513 · see citing works
The Free Radical Theory of Aging Matures
BECKMAN, K. B., & AMES, B. N. (1998) · Physiological Reviews · doi:10.1152/physrev.1998.78.2.547 · Cited by 3,879 · see citing works
The p66shc adaptor protein controls oxidative stress response and life span in mammals
Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Pandolfi, P. P., Lanfrancone, L., & Pelicci, P. G. (1999) · Nature · doi:10.1038/46311 · Cited by 1,712 · see citing works
Self-citationEnhanced Peroxynitrite Formation Is Associated with Vascular Aging
van der Loo, B., Labugger, R., Skepper, J. N., Bachschmid, M. M., Kilo, J., Powell, J. M., Palacios‐Callender, M., Erusalimsky, J. D., Quaschning, T., Maliñski, T., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.12.1731 · Cited by 674 · see citing works
Self-citationAge-Related Reduction of NO Availability and Oxidative Stress in Humans
Taddei, S., Virdis, A., Ghiadoni, L., Salvetti, G., Bernini, G., Magagna, A., & Salvetti, A. (2001) · Hypertension · doi:10.1161/01.hyp.38.2.274 · Cited by 664 · see citing works
Peroxynitrite‐mediated oxidative protein modifications
Ischiropoulos, H., & Al‐Mehdi, A. B. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00307-u · Cited by 610 · see citing works
Aging-Induced Phenotypic Changes and Oxidative Stress Impair Coronary Arteriolar Function
Csiszár, A., Ungvari, Z. I., Edwards, J. G., Kaminski, P. M., Wolin, M. S., Koller, Á., & Kaley, G. (2002) · Circulation Research · doi:10.1161/01.res.0000020401.61826.ea · Cited by 565 · see citing works
Mapping and Ablation of Ventricular Fibrillation Associated With Long-QT and Brugada Syndromes
Haı̈ssaguerre, M., Extramiana, F., Hocini, M., CAUCHEMEZ, B., Jaı̈s, P., Cabrera, J. Á., Farre, G., Leenhardt, A., Sanders, P., Scavée, C., et al. (2003) · Circulation · doi:10.1161/01.cir.0000088781.99943.95 · Cited by 518 · see citing works
Superoxide Excess in Hypertension and Aging
Hamilton, C., Brosnan, M. J., McIntyre, M., Graham, D., & Dominiczak, A. F. (2001) · Hypertension · doi:10.1161/01.hyp.37.2.529 · Cited by 438 · see citing works
Trinei, M., Giorgio, M., Cicalese, A., Barozzi, S., Ventura, A., Migliaccio, E., Milia, E., Padura, I. M., Raker, V. A., Maccarana, M., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205513 · Cited by 436 · see citing works
Self-citationSuperoxide Reacts with Nitric Oxide to Nitrate Tyrosine at Physiological pH via Peroxynitrite
Reiter, C. D., Teng, R., & Beckman, J. S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m910433199 · Cited by 385 · see citing works
Napoli, C., Martin-Padura, I., de Nigris, F., Giorgio, M., Mansueto, G., Somma, P., Condorelli, M., Sica, G., De Rosa, G., & Pelicci, P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0336359100 · Cited by 380 · see citing works
Self-citationProtein Nitration in Cardiovascular Diseases
Turko, I. V., & Murad, F. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.4.619 · Cited by 372 · see citing works
Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats.
Cosentino, F., Patton, S. R., d’Uscio, L. V., Werner, E. R., Werner‐Felmayer, G., Moreau, P. R., Maliñski, T., & Lüscher, T. F. (1998) · Journal of Clinical Investigation · doi:10.1172/jci650 · Cited by 351 · see citing works
Self-citationCernadas, M. R., de Miguel, L. S., Garcı́a-Durán, M., González-Fernández, F., Millás, I., Montón, M., Rodrigo, J., Rico, L., Fernández, A. P., de Frutos, T., et al. (1998) · Circulation Research · doi:10.1161/01.res.83.3.279 · Cited by 310 · see citing works
Atherosclerosis and the Two Faces of Endothelial Nitric Oxide Synthase
Wever, R. M. F., Lüscher, T. F., Cosentino, F., & Rabelink, T. J. (1998) · Circulation · doi:10.1161/01.cir.97.1.108 · Cited by 292 · see citing works
Self-citationZou, M., Martin, C., & Ullrich, V. (1997) · Biological Chemistry · doi:10.1515/bchm.1997.378.7.707 · Cited by 289 · see citing works
Zou, M.-H., Shi, C., & Cohen, R. A. (2002) · Diabetes · doi:10.2337/diabetes.51.1.198 · Cited by 262 · see citing works
Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery.
Tschudi, M. R., Barton, M., Bersinger, N. A., Moreau, P. R., Cosentino, F., Noll, G., Maliñski, T., & Lüscher, T. F. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118872 · Cited by 260 · see citing works
Self-citationNot all Shc's roads lead to Ras
Bonfini, L., Migliaccio, E., Pelicci, G., Lanfrancone, L., & Pelicci, P. G. (1996) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(96)10033-5 · Cited by 240 · cited 1× · see citing works
“fully elucidated and might involve (1) gradual loss of anti-”
BackgroundSelf-citationDevelopment of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1low mice)
Vannucchi, A. M., Bianchi, L., Cellai, C., Paoletti, F., Rana, R. A., Lorenzini, R., Migliaccio, G., & Migliaccio, A. R. (2002) · Blood · doi:10.1182/blood-2002-06-1913 · Cited by 224 · see citing works
Anatomic Heterogeneity of Vascular Aging
Barton, M., Cosentino, F., Brandes, R. P., Moreau, P. R., Shaw, S., & Lüscher, T. F. (1997) · Hypertension · doi:10.1161/01.hyp.30.4.817 · Cited by 222 · see citing works
Self-citationTyrosine Nitration by Simultaneous Generation of ⋅NO and O⨪2 under Physiological Conditions
Goldstein, S., Czapski, G., Lind, J., & Merényi, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.5.3031 · Cited by 177 · see citing works
Zou, M., Leist, M., & Ullrich, V. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65390-4 · Cited by 163 · see citing works
Circulating and cellular markers of endothelial dysfunction with aging in rats
Challah, M., Nadaud, S., Philippe, M., Battle, T., Soubrier, F., Corman, B., & Michel, J. (1997) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1997.273.4.h1941 · Cited by 104 · see citing works
Zou, M.-H., & Bachschmid, M. M. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.1.135 · Cited by 80 · see citing works
Self-citationYan, Z.-Q., Sirsjö, A., Bochaton‐Piallat, M., et al. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.12.2854 · Cited by 73 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Nitric Oxide and Peroxynitrite in Health and Disease
Pacher, P., Beckman, J. S., & Liaudet, L. (2007) · Physiological Reviews · doi:10.1152/physrev.00029.2006 · Cited by 6,390 · see citing works
Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals?
Giorgio, M., Trinei, M., Migliaccio, E., & Pelicci, P. G. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2240 · Cited by 1,441 · see citing works
Self-citationCysteine-Mediated Redox Signaling: Chemistry, Biology, and Tools for Discovery
Paulsen, C. E., & Carroll, K. S. (2013) · Chemical Reviews · doi:10.1021/cr300163e · Cited by 1,283 · see citing works
Giorgio, M., Migliaccio, E., Orsini, F., Paolucci, D., Moroni, M., Contursi, C., Pelliccia, G., Luzi, L., Minucci, S., Marcaccio, M., et al. (2005) · Cell · doi:10.1016/j.cell.2005.05.011 · Cited by 1,176 · see citing works
“…et al., 1999; Trinei et al., 2002). t Intracellular ROS levels are decreased in p66Shc−/− m cells, as revealed by the reduced oxidation of ROS-senc sitive probes and the reduced accumulation of endogeR nous markers of oxidative stress (8-oxo-guanosine) i(Trinei et al., 2002; Francia et al., 2004).”
Self-citationMitochondrial and metabolic dysfunction in ageing and age-related diseases
Amorim, J. A., Coppotelli, G., Rolo, A. P., Palmeira, C. M., Ross, J. M., & Sinclair, D. A. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00626-7 · Cited by 990 · see citing works
Wang (2012) · doi:10.1161/circresaha.111.261388 · Cited by 957 · see citing works
Ungvari, Z., Tarantini, S., Donato, A. J., Galvan, V., & Csiszar, A. (2018) · Circulation Research · doi:10.1161/circresaha.118.311378 · Cited by 919 · see citing works
“Many of the results of vascular oxidative stress are mediated via production of the highly reactive oxidant peroxynitrite—the reaction product of NO and superoxide,(39,40) which has been well documented in older endothelial cells and arteries.(13,15,20,22) The mechanisms by which peroxynitrite contributes to vascular…”
BackgroundMitochondrial Dysfunction in Atherosclerosis
Madamanchi, N. R., & Runge, M. S. (2007) · Circulation Research · doi:10.1161/01.res.0000258450.44413.96 · Cited by 794 · see citing works
Aging and vascular endothelial function in humans
Seals, D. R., Jablonski, K. L., & Donato, A. J. (2011) · Clinical Science · doi:10.1042/cs20100476 · Cited by 725 · see citing works
Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease
Donato, A. J., Machin, D. R., & Lesniewski, L. A. (2018) · Circulation Research · doi:10.1161/circresaha.118.312563 · Cited by 699 · see citing works
Mitochondria-Ros Crosstalk in the Control of Cell Death and Aging
Marchi, S., Giorgi, C., Suski, J. M., Agnoletto, C., Bononi, A., Bonora, M., Marchi, E. D., Missiroli, S., Patergnani, S., Poletti, F., et al. (2011) · Journal of Signal Transduction · doi:10.1155/2012/329635 · Cited by 639 · see citing works
“Accordingly, p66shc knockout mice are one of the best characterized genetic model of longevity, is being more resistant to oxidative stress [157] and protected against age-dependent, ROS-mediated cardiovascular complications induced by diabetes [158–160].”
BackgroundCoronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases
Buono, M. G. D., Montone, R. A., Camilli, M., Carbone, S., Narula, J., Lavie, C. J., Niccoli, G., & Crea, F. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.07.042 · Cited by 662 · see citing works
“In mammals, p66Shc is a pro apoptotic protein that further enhances ROS generation by altering the mitochondrial bio energetic properties(6,8,9).”
BackgroundThe Aging Cardiovascular System
Paneni, F., Diaz Cañestro, C., Libby, P., Lüscher, T. F., & Camici, G. G. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.01.064 · Cited by 618 · see citing works
Mitochondria in health, disease, and aging
Harrington, J. S., Ryter, S. W., Plataki, M. E., Price, D. R., & Choi, A. M. K. (2023) · Physiological Reviews · doi:10.1152/physrev.00058.2021 · Cited by 622 · see citing works
Oxidative stress and vascular inflammation in aging
Assar, M. E., Angulo, J., & Rodríguez‐Mañas, L. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.003 · Cited by 576 · see citing works
Direct Evidence of Endothelial Oxidative Stress With Aging in Humans
Donato, A. J., Eskurza, I., Silver, A., Levy, A., Pierce, G. L., Gates, P. E., & Seals, D. R. (2007) · Circulation Research · doi:10.1161/01.res.0000269183.13937.e8 · Cited by 558 · see citing works
Cellular and molecular biology of aging endothelial cells
Donato, A. J., Morgan, R. G., Walker, A. E., & Lesniewski, L. A. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.01.021 · Cited by 538 · see citing works
“Supporting the critical role of NFκB in age-related inflammation dependent endothelial dysfunction is evidence that pharmacological inhibition of NFκB signaling significantly reduces cytokines and enhances EDD in old mice and humans [113, 121, 122].”
InfluentialMechanisms of Vascular Aging: New Perspectives
Ungvari, Z. I., Kaley, G., de Cabo, R., Sonntag, W. E., & Csiszár, A. (2010) · The Journals of Gerontology Series A · doi:10.1093/gerona/glq113 · Cited by 534 · see citing works
Mapping and Ablation of Ventricular Fibrillation Associated With Long-QT and Brugada Syndromes
Haı̈ssaguerre, M., Extramiana, F., Hocini, M., CAUCHEMEZ, B., Jaı̈s, P., Cabrera, J. Á., Farre, G., Leenhardt, A., Sanders, P., Scavée, C., et al. (2003) · Circulation · doi:10.1161/01.cir.0000088781.99943.95 · Cited by 518 · see citing works
Orchestrating Redox Signaling Networks through Regulatory Cysteine Switches
Paulsen, C. E., & Carroll, K. S. (2009) · ACS Chemical Biology · doi:10.1021/cb900258z · Cited by 476 · see citing works
Sirtuins, a promising target in slowing down the ageing process
Grabowska, W., Sikora, E., & Bielak-Zmijewska, A. (2017) · Biogerontology · doi:10.1007/s10522-017-9685-9 · Cited by 470 · see citing works
“Ageing-initiated P66shcmediated endothelial dysfunction was shown both in clinical trials and animal experiments, however, not in P66shc knockout mice (Francia et al. 2004).”
BackgroundEndothelial dysfunction and angiogenesis impairment in the ageing vasculature
Ungvari, Z. I., Tarantini, S., Kiss, T., Wren, J. D., Giles, C. B., Griffin, C. T., Murfee, W. L., Pacher, P., & Csiszár, A. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0030-z · Cited by 478 · see citing works
Ageing, metabolism and cardiovascular disease
Costantino, S., Paneni, F., & Cosentino, F. (2015) · The Journal of Physiology · doi:10.1113/jp270538 · Cited by 465 · see citing works
“This phenomenon was largely explained by preservation of nitric oxide availability in mice lacking the p66Shc gene (Francia et al. 2004).”
BackgroundSelf-citationMolecular Biology of Atherosclerosis
Hopkins, P. N. (2013) · Physiological Reviews · doi:10.1152/physrev.00004.2012 · Cited by 456 · see citing works
Inflammation and endothelial dysfunction during aging: role of NF-κB
Csiszar, A., Wang, M., Lakatta, E. G., & Ungvari, Z. (2008) · Journal of Applied Physiology · doi:10.1152/japplphysiol.90470.2008 · Cited by 441 · see citing works
Reactive Oxygen Species in Skeletal Muscle Signaling
Barbieri, E., & Sestili, P. (2011) · Journal of Signal Transduction · doi:10.1155/2012/982794 · Cited by 414 · see citing works
Thomas, S. R., Witting, P. K., & Drummond, G. R. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2008.2027 · Cited by 383 · see citing works
“Deficiency of the p66Shc gene protects against atherosclerosis in mice fed a high-fat diet (366) and ROS-induced impairment of EDNO bioactivity and endothelial dysfunction associated with aging (152, 551) and hyperglycemia (68).”
Lim, H. Y., Lim, S. Y., Tan, C. K., Thiam, C. H., Goh, C. C., Carbajo, D., Chew, S. H. S., See, P., Chakarov, S., Wang, X. N., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.06.008 · Cited by 384 · see citing works
Ungvari, Z. I., Orosz, Z. Z., Labinskyy, N., Rivera, A., Xiangmin, Z., Smith, K. E., & Csiszár, A. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01346.2006 · Cited by 347 · see citing works
Mitochondria, endothelial cell function, and vascular diseases
Tang, X., Luo, Y., Chen, H., & Liu, D. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00175 · Cited by 345 · see citing works
“…function is evident from the observations that p66Shc knockout mice are protected against ROS-dependent, age-related endothelial dysfunction (Francia et al., 2004), hyperglycemia-induced endothelial dysfunction (Zhou et al., 2011b), as well as high-fat-induced Frontiers in Physiology |…”
BackgroundVascular biology of ageing—Implications in hypertension
Harvey, A., Montezano, A. C., & Touyz, R. M. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.04.011 · Cited by 330 · see citing works
“Mice lacking p66shc gene display a 30% increase in lifespan compared to wild-type controls due to prevention of oxidative stress and improved endothelial function [70,71].”
BackgroundEffects of aging on angiogenesis
Lähteenvuo, J., & Rosenzweig, A. (2012) · Circulation Research · doi:10.1161/circresaha.111.246116 · Cited by 292 · see citing works
Role of the GH/IGF-1 axis in lifespan and healthspan: Lessons from animal models
Berryman, D. E., Christiansen, J. S., Johannsson, G., Thorner, M. O., & Kopchick, J. J. (2008) · Growth Hormone & IGF Research · doi:10.1016/j.ghir.2008.05.005 · Cited by 288 · see citing works
Zhou, S., Chen, H., Wan, Y.-Z., Zhang, Q.-J., Wei, Y.-S., Huang, S., Liu, J., Lu, Y., Zhang, Z., Yang, R., et al. (2011) · Circulation Research · doi:10.1161/circresaha.111.243592 · Cited by 273 · see citing works
Ungvari, Z. I., Bailey‐Downs, L. C., Sosnowska, D., Gautam, T., Koncz, P., Losonczy, G., Ballabh, P., de Cabo, R., Sonntag, W. E., & Csiszár, A. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01134.2010 · Cited by 274 · see citing works
Papaconstantinou, J. (2019) · Cells · doi:10.3390/cells8111383 · Cited by 259 · see citing works
Paneni, F., Mocharla, P., Akhmedov, A. T., Costantino, S., Osto, E., Volpe, M., Lüscher, T. F., & Cosentino, F. (2012) · Circulation Research · doi:10.1161/circresaha.112.266593 · Cited by 254 · see citing works
Self-citationCamici, G. G., Schiavoni, M., Francia, P., Bachschmid, M., Martin-Padura, I., Hersberger, M., Tanner, F. C., Pelicci, P., Volpe, M., Anversa, P., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609656104 · Cited by 249 · see citing works
Self-citationVascular Oxidative Stress: Impact and Therapeutic Approaches
Sena, C. M., Leandro, A., Azul, L., Seiça, R. M. F., & Perry, G. L. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01668 · Cited by 260 · see citing works
Radical medicine: treating ageing to cure disease
Finkel, T. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1763 · Cited by 234 · see citing works
“Similarly, the early oxidant-induced changes in vascular function that precede plaque formation were also absent in p66Shc −/− animal”
BackgroundMechanisms Underlying Caloric Restriction and Lifespan Regulation
Ungvari, Z. I., Parrado‐Fernández, C., Csiszár, A., & de Cabo, R. (2008) · Circulation Research · doi:10.1161/circresaha.107.168369 · Cited by 239 · see citing works
Mikhed, Y., Daiber, A., & Steven, S. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms160715918 · Cited by 257 · see citing works
“Extensive research revealed that p66Shc−/− mice are protected from age-dependent endothelial dysfunction [184] as well as age-related risk factors such as diabetes and hypercholesterolemia.”
BackgroundKalpage, H. A., Bazylianska, V., Recanati, M., Fite, A., Liu, J., Wan, J., Mantena, N., Malek, M. H., Podgorski, I., Heath, E., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201801417r · Cited by 226 · see citing works
The Role of Oxidative Stress and Inflammation in Cardiovascular Aging
Wu, J., Xia, S., Kalionis, B., Wan, W., & Sun, T. (2014) · BioMed Research International · doi:10.1155/2014/615312 · Cited by 220 · see citing works
“p66Shc−/− signaling is required to induce a ROS-driven vascular senescent phenotype [39].”
BackgroundMethodInfluentialVasculoprotective Effects of Anti-Tumor Necrosis Factor-α Treatment in Aging
Csiszár, A., Labinskyy, N., Smith, K. E., Rivera, A., Orosz, Z. Z., & Ungvari, Z. I. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.060708 · Cited by 214 · see citing works
“increasing the activity of NAD(P)H oxidase (Figure 2), thereby increasing NO breakdown and decreasing its bioavailability.(4,6,7,14) We found that neutralization of TNF- by chronic treatment with etanercept improved endothelial function (Figure 1B) and NO mediation in aged arteries (Figure 1C) and reduced vascular NAD…”
Role of urate, xanthine oxidase and the effects of allopurinol in vascular oxidative stress
Casella, G. (2009) · Vascular Health and Risk Management · doi:10.2147/vhrm.s4265 · Cited by 215 · see citing works
“This has been demonstrated in animal studies using p66 knockout mice which demonstrate reduced aortic endothelial cell superoxide production and a 30% prolonged lifespan.(6) The precise role of p66 remains unclear but in studies looking at its effects on the p53 signaling pathway demonstrate that it is involved V as c…”
Regulation of Endothelial Function by Mitochondrial Reactive Oxygen Species
Widlansky, M. E., & Gutterman, D. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3642 · Cited by 211 · see citing works
“Data demonstrating an increased life span and protection from agerelated endothelial dysfunction in p66-knockout animals suggest p66 as a potential target as well (47, 101).”
BackgroundMarzetti, E., Csiszár, A., Dutta, D., Balagopal, G., Calvani, R., & Leeuwenburgh, C. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00936.2012 · Cited by 197 · see citing works
Menini, S., Amadio, L., Oddi, G., Ricci, P. C., Pesce, C. M., Pugliese, F. R., Giorgio, M., Migliaccio, E., Pelicci, P. G., Iacobini, C., et al. (2006) · Diabetes · doi:10.2337/db05-1477 · Cited by 183 · see citing works
“More recently, p66 ablation was found to protect from tissue damage (and apoptosis of endothelial cells and myofibers) following acute ischemia or ischemia/reperfusion (22) and endothelial dysfunction associated with aging (23).”
BackgroundSelf-citationTrougakos, I. P., & Gonos, E. S. (2006) · Free Radical Research · doi:10.1080/10715760600902310 · Cited by 184 · see citing works
“The level of p66 decreased with advanced age [73] and ROS-mediated dysfunction in aortic endothelial cells was prevented in p66 mice [74].”
BackgroundFinal Common Molecular Pathways of Aging and Cardiovascular Disease
Cosentino, F., Francia, P., Camici, G. G., Pelicci, P. G., Volpe, M., & Lüscher, T. F. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.156059 · Cited by 169 · see citing works
Self-citationPathophysiology of Coronary Microvascular Dysfunction
Crea, F., Montone, R. A., & Rinaldi, R. (2021) · Circulation Journal · doi:10.1253/circj.cj-21-0848 · Cited by 169 · see citing works
Assessment and pathophysiology of microvascular disease: recent progress and clinical implications
Masi, S., Rizzoni, D., Taddei, S., Widmer, R. J., Montezano, A. C. I., Lüscher, T. F., Schiffrin, E. L., Touyz, R. M., Paneni, F., Lerman, A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa857 · Cited by 162 · see citing works
p66Shc-generated Oxidative Signal Promotes Fat Accumulation
Berniakovich, I., Trinei, M., Stendardo, M., Migliaccio, E., Minucci, S., Bernardi, P., Pelicci, P. G., & Giorgio, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804362200 · Cited by 161 · see citing works
Self-citationCarpi, A., Menabò, R., Kaludercic, N., Pelicci, P. G., Lisa, F. D., & Giorgio, M. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.04.001 · Cited by 153 · see citing works
Self-citationAdaptive mechanisms to oxidative stress during aging
Yu, B. P., & Chung, H. Y. (2006) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2006.01.023 · Cited by 153 · see citing works
The Mammalian Longevity-associated Gene Product p66 Regulates Mitochondrial Metabolism
Nemoto, S., Combs, C. A., French, S. A., Ahn, B., Fergusson, M. M., Balaban, R. S., & Finkel, T. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511626200 · Cited by 147 · see citing works
Kirkman, D. L., Robinson, A. T., Rossman, M. J., Seals, D. R., & Edwards, D. G. (2021) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00917.2020 · Cited by 146 · see citing works
Vascular Dysfunction in Aging: Potential Effects of Resveratrol, an Anti- Inflammatory Phytoestrogen
Labinskyy, N., Csiszár, A., Veress, G., Stef, G., Pacher, P., Oroszi, G., WU, J. M., & Ungvari, Z. I. (2006) · Current Medicinal Chemistry · doi:10.2174/092986706776360987 · Cited by 138 · see citing works
Kumar, A., Kumar, S., Vikram, A., Hoffman, T. A., Naqvi, A., Lewarchik, C. M., Kim, Y., & Irani, K. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.113.301765 · Cited by 137 · see citing works
Vascular Hyperpermeability and Aging
Oakley, R. P. (2014) · Aging and Disease · doi:10.14336/ad.2014.0500114 · Cited by 135 · see citing works
“It has been demonstrated that biomarkers of oxidant damage, increased levels of nitrotyrosine were observed in human aged vascular endothelial cells [50], Moreover, oxidative stress markers were also observed in the arteries of aged animals [50,51], suggesting that aging is indeed associated with increased formation o…”
BackgroundSuperoxide‐lowering therapy with TEMPOL reverses arterial dysfunction with aging in mice
Fleenor, B. S., Seals, D. R., Zigler, M. L., & Sindler, A. L. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00783.x · Cited by 133 · see citing works
“…and electronic paramagnetic resonance spectroscopy (Rippe et al., 2010; Sindler et al., 2011) suggesting, along with earlier reports (Hamilton et al., 2001; Francia et al., 2004; Lesniewski et al., 2009; Sindler et al., 2009), that this is a key contributor to oxidative stress in arterial aging.”
BackgroundPermanent embryo arrest: molecular and cellular concepts
Betts, D. H., & Madan, P. (2008) · Molecular Human Reproduction · doi:10.1093/molehr/gan035 · Cited by 131 · see citing works
“…genetic or pharmacological modification of the p66Shc pathway by promoting stress resistance could have direct implications for various age-related diseases and infertility in humans (Napoli et al., 2003; Francia et al., 2004; Graiani et al., 2005; Berry et al., 2006; Tothova et al., 2007).”
BackgroundFactors and Pathways Modulating Endothelial Cell Senescence in Vascular Aging
Hwang, H. J., Kim, N., Herman, A. B., Gorospe, M., & Lee, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231710135 · Cited by 135 · see citing works
“In aortic rings from young and old mice, P66shc was implicated in protecting against an age-dependent impairment of EC relaxation in response to acetylcholine [138].”
BackgroundPagnin, E., Fadini, G., de Toni, R., Tiengo, A., Calò, L., & Avogaro, A. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1283 · Cited by 127 · see citing works
Noh, Y. H., Baek, J. Y., Jeong, W., Rhee, S. G., & Chang, T.-S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808981200 · Cited by 126 · see citing works
Apoptosis and Aging: Role of p66 <sup>Shc</sup> Redox Protein
Migliaccio, E., Giorgio, M., & Pelicci, P. G. (2006) · Antioxidants & Redox Signaling · doi:10.1089/ars.2006.8.600 · Cited by 123 · see citing works
“Further studies are required to elucidate the p66 Shc role in regulation of intracellular redox balance and its role in integration of cellular pathways, that are relevant to the , which regulate Ras (growth) and p53 (apoptosis).”
Self-citationwang, L., Quan, N., Sun, W., Chen, X., Cates, C. A., Rousselle, T. V., Zhou, X., Zhao, X., & Li, J. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy033 · Cited by 122 · see citing works
“pShc(66) knockout mice have enhanced resistance to oxidative stress and a 30% increase in lifespan; pShc(66) augments reactive oxygen species (ROS)-dependent endothelial dysfunction induced by aging.(65,66) Therefore, endothelial function can be preserved and vascular aging can be delayed by inhibiting pShc.”
Insulin/IGF-1 and ROS signaling pathway cross-talk in aging and longevity determination
Papaconstantinou, J. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.11.025 · Cited by 124 · see citing works
“These p66shc knockouts exhibit esistance to exogenous oxidative stress in vivo, and their cells in ulture show lower levels of ROS production (Francia et al., 2004; igliaccio et al., 1999; Napoli et al., 2003; Nemoto and Finkel, 2002; rinei et al., 2002).”
BackgroundEndothelium, aging, and hypertension
Taddei, S., Virdis, A., Ghiadoni, L., Versari, D., & Salvetti, A. (2006) · Current Hypertension Reports · doi:10.1007/s11906-006-0045-4 · Cited by 122 · see citing works
Nanoparticles in the diagnosis and treatment of vascular aging and related diseases
Xu, H., Li, S., & Liu, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01082-z · Cited by 122 · see citing works
“The production of ROS and reactive nitrogen species (RNS) increases with vasculature aging.(148,149) ROS production in vascular walls is predominantly due to the actions of NADPH oxidase (NOX), xanthine oxidase, and uncoupled endothelial synthase (eNOS).”
BackgroundNoujaim (2004) · doi:10.1161/01.cir.0000146785.15995.67 · Cited by 110 · see citing works
Csiszár, A., Pacher, P., Kaley, G., & Ungvari, Z. I. (2005) · Current Vascular Pharmacology · doi:10.2174/1570161054368616 · Cited by 112 · see citing works
“One of the consequences of increased oxidative stress in aging is a functional inactivation of NO by high concentrations of O2, resulting in an enhanced ONOO− formation [3,4,7,8].”
BackgroundInfluentialNitric Oxide, Oxidative Stress, and p66Shc Interplay in Diabetic Endothelial Dysfunction
Magenta, A., Greco, S., Capogrossi, M. C., Gaetano, C., & Martelli, F. (2014) · BioMed Research International · doi:10.1155/2014/193095 · Cited by 110 · see citing works
“reduced levels of systemic (isoprostane) and tissue (nitrotyrosine, 8-oxo-dG) oxidative stress markers [68, 76, 77] and enhanced resistance to oxidative stress induced by hypercholesterolemia [78], angiotensin II [79], carbon tetrachloride, and ethanol [80].”
BackgroundPaneni, F., Osto, E., Costantino, S., Mateescu, B., Schumacher, S. B., Coppolino, G., Perna, E., Mocharla, P. S., Akhmedov, A. T., Kubant, R., et al. (2013) · Circulation · doi:10.1161/circulationaha.112.000826 · Cited by 111 · see citing works
Self-citationMitochondria and aging in the vascular system
Ungvari, Z., Sonntag, W. E., & Csiszar, A. (2010) · Journal of Molecular Medicine · doi:10.1007/s00109-010-0667-5 · Cited by 103 · see citing works
Vascular ageing: Underlying mechanisms and clinical implications
Laina, A., Stellos, K., & Stamatelopoulos, K. S. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.06.007 · Cited by 103 · see citing works
“The role of p66 in vascular ageing was investigated in aortic rings from young and old mice showing that age-dependent impairment of endothelial relaxation in response to acetylcholine was not detected in p66 knockout mice which were also found to be protected against the age-related decline in NO release (Francia et…”
BackgroundOxidative stress in vascular senescence: lessons from successfully aging species
Ungvari, Z. I. (2008) · Frontiers in bioscience · doi:10.2741/3064 · Cited by 100 · see citing works
“Aging-induced vascular oxidative stress seems to be associated with a pro-oxidant shift in vascular phenotype, including an increased expression of iNOS (12, 24) and increased activity of NAD (P)H oxidases (7, 11, 23, 25) and/or other oxidase mechanisms (26) and a downregulation of antioxidants, such as ecSOD (10).”
BackgroundInfluentialBurger, D. E., Kwart, D. G., Montezano, A. C. I., Read, N. C., Kennedy, C., Thompson, C. S., & Touyz, R. M. (2012) · Journal of the American Heart Association · doi:10.1161/jaha.112.001842 · Cited by 99 · see citing works
Xiong, Y., Liu, T., WANG, S., Chi, H., Chen, C., & Zheng, J. (2016) · Gene · doi:10.1016/j.gene.2016.10.011 · Cited by 99 · see citing works
“A p66Shc deficiency has a protective effect on agingassociated endothelial dysfunction, which is related to upregulation of iNOS (Francia et al., 2004).”
BackgroundInfluentialKim, C., Kim, Y., Naqvi, A., Kumar, S., Hoffman, T. A., Jung, S.-B., Kumar, A., Jeon, B. H., McNamara, D. M., & Irani, K. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr250 · Cited by 96 · see citing works
“[19] Francia P, delli Gatti C, Bachschmid M, Martin-Padura I, Savoia C, Migliaccio E, et al.”
BackgroundEndothelial cell senescence and thrombosis: Ageing clots
Bochenek, M. L., Schütz, E., & Schäfer, K. (2016) · Thrombosis Research · doi:10.1016/j.thromres.2016.09.019 · Cited by 96 · see citing works
Role of endothelial NAD+deficiency in age-related vascular dysfunction
Csiszár, A., Tarantini, S., Yabluchanskiy, A., Balasubramanian, P., Kiss, T., Farkas, E., Baur, J. A., & Ungvari, Z. I. (2019) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00039.2019 · Cited by 93 · see citing works
Effect of Aging, MnSOD Deficiency, and Genetic Background on Endothelial Function
Brown, K. A., Didion, S. P., Andresen, J. J., & Faraci, F. M. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.146852 · Cited by 90 · see citing works
Epigenetics and Immunometabolism in Diabetes and Aging
Guzik, T. J., & Cosentino, F. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7299 · Cited by 93 · see citing works
“Accordingly, NO availability was not reduced in aged p66 mice (38).”
BackgroundSelf-citationLesniewski, L. A., Connell, M., Durrant, J., Folian, B. J., Anderson, M. C., Donato, A. J., & Seals, D. R. (2009) · The Journals of Gerontology Series A · doi:10.1093/gerona/gln049 · Cited by 91 · see citing works
Xiong, Y., Yu, Y., Montani, J., Yang, Z., & Ming, X. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.113.000096 · Cited by 91 · see citing works
“These mechanisms are implicated in organism aging and aging-associated pathologies, including oxidative stress, cellular senescence and apoptosis, and vascular disease.(11,19) Interestingly, arginase-II (Arg-II), an L-arginine ureahydrolase metabolizing L-arginine to urea and L-ornithine, is mainly localized in the mi…”
BackgroundTang, Y., Xu, J., Qu, W., Peng, X., Peng, X., Yang, X., Ying, C., Sun, X., & Hao, L. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2011.08.008 · Cited by 90 · see citing works
“It is known that increased ROS production in aging vessels is mainly caused by the enhanced activity and/or expression of NADPH oxidase [26,57–59].”
BackgroundTrinei, M., Berniakovich, I., Beltrami, E., Migliaccio, E., Fassina, A., Pelicci, P. G., & Giorgio, M. (2009) · Aging · doi:10.18632/aging.100057 · Cited by 88 · see citing works
“Likewise, p66-/- mice show diminished levels of both systemic (isoprostane) and intracellular (nytrotyrosines, 8-oxo-dG) oxidative stress [14, 18, 19].”
BackgroundSelf-citationChen, Z., Yu, J., Fu, M., Dong, R., Yang, Y., Luo, J., Hu, S., Li, W., Xu, X., & Tu, L. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113951 · Cited by 85 · see citing works
Pharmacological Strategies to Retard Cardiovascular Aging
Alfaras, I., Germanio, C. D., Bernier, M., Csiszár, A., Ungvari, Z. I., Lakatta, E. G., & de Cabo, R. (2016) · Circulation Research · doi:10.1161/circresaha.116.307475 · Cited by 87 · see citing works
Goldsmith, T. C. (2008) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2008.02.035 · Cited by 87 · see citing works
Mitochondrial longevity pathways
Raffaello, A., & Rizzuto, R. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2010.10.007 · Cited by 87 · see citing works
Endothelial progenitor cells in diabetes mellitus
Menegazzo, L., Albiero, M., Avogaro, A., & Fadini, G. P. (2012) · BioFactors · doi:10.1002/biof.1016 · Cited by 86 · see citing works
Berry, A., Capone, F., Giorgio, M., Pelicci, P. G., de Kloet, E. R., Alleva, E., Minghetti, L., & Cirulli, F. (2007) · Experimental Gerontology · doi:10.1016/j.exger.2006.05.018 · Cited by 81 · see citing works
“Likewise, p66mice have diminished levels of both systemic (isoprostane) and intracellular (nytrotyrosines, 8-oxo-guanosine) oxidative stress (Trinei et al., 2002; Napoli et al., 2003; Francia et al., 2004).”
BackgroundInfluentialSelf-citationNovel role of p66Shc in ROS-dependent VEGF signaling and angiogenesis in endothelial cells
Oshikawa, J., Kim, S.-J., Furuta, E., Caliceti, C., Chen, G., McKinney, R. D., Kuhr, F., Levitan, I., Fukai, T., & Ushio‐Fukai, M. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00739.2011 · Cited by 85 · see citing works
Spescha, R. D., Shi, Y., Wegener, S., Keller, S., Weber, B., Wyss, M. T., Lauinger, N. D., Tabatabai, G., Paneni, F., Cosentino, F., et al. (2012) · European Heart Journal · doi:10.1093/eurheartj/ehs331 · Cited by 83 · see citing works
Self-citationP66Shc-Induced MicroRNA-34a Causes Diabetic Endothelial Dysfunction by Downregulating Sirtuin1
Li, Q., Kim, Y., Vikram, A., Kumar, S., Kassan, M., Gabani, M. H., Lee, S. K., Jacobs, J. S., & Irani, K. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.308321 · Cited by 83 · see citing works
“Inactivation of p66Shc confers resistance to oxidative stress and protects mice from age-associated and diabetic vascular endothelial dysfunction.(11,12) Interestingly, p66Shc is regulated by Sirt1 in DM.”
BackgroundXiao, Y., Xia, J., Cheng, J., Huang, H., Zhou, Y., Yang, X., Su, X., Ke, Y., & Ling, W. (2019) · Circulation · doi:10.1161/circulationaha.118.036336 · Cited by 82 · see citing works
P53 Impairs Endothelium-Dependent Vasomotor Function Through Transcriptional Upregulation of P66shc
Kim, C., Jung, S.-B., Naqvi, A., Hoffman, T. A., DeRicco, J. S., Yamamori, T., Cole, M. P., Jeon, B. H., & Irani, K. (2008) · Circulation Research · doi:10.1161/circresaha.108.181644 · Cited by 81 · see citing works
- 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 › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
