spacer gif spacer gif spacer gif spacer gif spacer gif
 QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online May 4, 2004
doi: 10.1242/10.1242/jcs.01097


Journal of Cell Science 117, 2417-2426 (2004)
Published by The Company of Biologists 2004
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kurz, D. J.
Right arrow Articles by Erusalimsky, J. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kurz, D. J.
Right arrow Articles by Erusalimsky, J. D.
Social Bookmarking
 Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Research Article

Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells

David J. Kurz1,3,*, Stephanie Decary1,*, Ying Hong1,2, Elisabeth Trivier1, Alexander Akhmedov3 and Jorge D. Erusalimsky1,2,{ddagger}

1 Department of Medicine, University College London, 5 University Street, London, WC1E 6JF, UK
2 The Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK
3 Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich, Switzerland

{ddagger} Author for correspondence (e-mail: j.erusalimsky{at}ucl.ac.uk)

Accepted 9 January 2004

Replicative senescence and oxidative stress have been implicated in ageing, endothelial dysfunction and atherosclerosis. Replicative senescence is determined primarily by telomere integrity. In endothelial cells the glutathione redox-cycle plays a predominant role in the detoxification of peroxides. The aim of this study was to elucidate the role of the glutathione-dependent antioxidant system on the replicative capacity and telomere dynamics of cultured endothelial cells. Human umbilical vein endothelial cells were serially passaged while exposed to regular treatment with 0.1 µM tert-butyl hydroperoxide, a substrate of glutathione peroxidase, or 10 µM L-buthionine-[S,R]-sulphoximine, an inhibitor of glutathione synthesis. Both treatments induced intracellular oxidative stress but had no cytotoxic or cytostatic effects. Nonetheless, treated cultures entered senescence prematurely (30 versus 46 population doublings), as determined by senescence-associated ß-galactosidase staining and a sharp decrease in cell density at confluence. In cultures subjected to oxidative stress terminal restriction fragment (TRF) analysis demonstrated faster telomere shortening (110 versus 55 bp/population doubling) and the appearance of distinct, long TRFs after more than 15-20 population doublings. Fluorescence in situ hybridisation analysis of metaphase spreads confirmed the presence of increased telomere length heterogeneity, and ruled out telomeric end-to-end fusions as the source of the long TRFs. The latter was also confirmed by Bal31 digestion of genomic DNA. Similarly, upregulation of telomerase could not account for the appearance of long TRFs, as oxidative stress induced a rapid and sustained decrease in this activity. These findings demonstrate a key role for glutathione-dependent redox homeostasis in the preservation of telomere function in endothelial cells and suggest that loss of telomere integrity is a major trigger for the onset of premature senescence under mild chronic oxidative stress.

Key words: Ageing, Endothelium, Oxidative stress, Glutathione, Telomere, Telomerase


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. J. Khan, S. Pham, Y. Wei, D. Mateo, M. St-Pierre, T. M. Fletcher, and R. I. Vazquez-Padron
Stress-induced senescence exaggerates postinjury neointimal formation in the old vasculature
Am J Physiol Heart Circ Physiol, January 1, 2010; 298(1): H66 - H74.
[Abstract] [Full Text] [PDF]


Home page
Ann Rheum DisHome page
A J van Zonneveld, H C de Boer, E P van der Veer, and T J Rabelink
Inflammation, vascular injury and repair in rheumatoid arthritis
Ann Rheum Dis, January 1, 2010; 69(Suppl_1): i57 - i60.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
W. Yin, J.-I. Park, and R. F. Loeser
Oxidative Stress Inhibits Insulin-like Growth Factor-I Induction of Chondrocyte Proteoglycan Synthesis through Differential Regulation of Phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK Signaling Pathways
J. Biol. Chem., November 13, 2009; 284(46): 31972 - 31981.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
H. Norell, T. Martins da Palma, A. Lesher, N. Kaur, M. Mehrotra, O. S. Naga, N. Spivey, S. Olafimihan, N. G. Chakraborty, C. Voelkel-Johnson, et al.
Inhibition of Superoxide Generation upon T-Cell Receptor Engagement Rescues Mart-127-35-Reactive T Cells from Activation-Induced Cell Death
Cancer Res., August 1, 2009; 69(15): 6282 - 6289.
[Abstract] [Full Text] [PDF]


Home page
Exp PhysiolHome page
J. D. Erusalimsky and C. Skene
Mechanisms of endothelial senescence
Exp Physiol, March 1, 2009; 94(3): 299 - 304.
[Abstract] [Full Text] [PDF]


Home page
J. Appl. Physiol.Home page
J. D. Erusalimsky
Vascular endothelial senescence: from mechanisms to pathophysiology
J Appl Physiol, January 1, 2009; 106(1): 326 - 332.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. Lee, R. Reddy, L. Barsky, J. Scholes, H. Chen, W. Shi, and B. Driscoll
Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice
Am J Physiol Lung Cell Mol Physiol, January 1, 2009; 296(1): L57 - L70.
[Abstract] [Full Text] [PDF]


Home page
Eur J Heart FailHome page
L. S.M. Wong, R. A. de Boer, N. J. Samani, D. J. van Veldhuisen, and P. van der Harst
Telomere biology in heart failure
Eur J Heart Fail, November 1, 2008; 10(11): 1049 - 1056.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
H. Ota, M. Eto, M. R. Kano, S. Ogawa, K. Iijima, M. Akishita, and Y. Ouchi
Cilostazol Inhibits Oxidative Stress-Induced Premature Senescence Via Upregulation of Sirt1 in Human Endothelial Cells
Arterioscler Thromb Vasc Biol, September 1, 2008; 28(9): 1634 - 1639.
[Abstract] [Full Text] [PDF]


Home page
Mol Hum ReprodHome page
D.H. Betts and P. Madan
Permanent embryo arrest: molecular and cellular concepts
Mol. Hum. Reprod., August 1, 2008; 14(8): 445 - 453.
[Abstract] [Full Text] [PDF]


Home page
J. Cell Sci.Home page
S. Ahmed, J. F. Passos, M. J. Birket, T. Beckmann, S. Brings, H. Peters, M. A. Birch-Machin, T. von Zglinicki, and G. Saretzki
Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress
J. Cell Sci., April 1, 2008; 121(7): 1046 - 1053.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
K. E. Herbert, Y. Mistry, R. Hastings, T. Poolman, L. Niklason, and B. Williams
Angiotensin II-Mediated Oxidative DNA Damage Accelerates Cellular Senescence in Cultured Human Vascular Smooth Muscle Cells via Telomere-Dependent and Independent Pathways
Circ. Res., February 1, 2008; 102(2): 201 - 208.
[Abstract] [Full Text] [PDF]


Home page
Nucleic Acids ResHome page
J. F. Passos, G. Saretzki, and T. von Zglinicki
DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?
Nucleic Acids Res., December 3, 2007; 35(22): 7505 - 7513.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Clin. Nutr.Home page
J B. Richards, A. M Valdes, J. P Gardner, D. Paximadas, M. Kimura, A. Nessa, X. Lu, G. L Surdulescu, R. Swaminathan, T. D Spector, et al.
Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women
Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1420 - 1425.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
M. Y.K. Lee, H.-F. Tse, C.-W. Siu, S.-G. Zhu, R. Y.K. Man, and P. M. Vanhoutte
Genomic Changes in Regenerated Porcine Coronary Arterial Endothelial Cells
Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2443 - 2449.
[Abstract] [Full Text] [PDF]


Home page
Diabetes CareHome page
N. Tentolouris, R. Nzietchueng, V. Cattan, G. Poitevin, P. Lacolley, A. Papazafiropoulou, D. Perrea, N. Katsilambros, and A. Benetos
White Blood Cells Telomere Length Is Shorter in Males With Type 2 Diabetes and Microalbuminuria
Diabetes Care, November 1, 2007; 30(11): 2909 - 2915.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
Q. Shi, G. B. Hubbard, R. S. Kushwaha, D. Rainwater, C. A. Thomas III, M. M. Leland, J. L. VandeBerg, and X. L. Wang
Endothelial senescence after high-cholesterol, high-fat diet challenge in baboons
Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2913 - H2920.
[Abstract] [Full Text] [PDF]


Home page
J. Leukoc. Biol.Home page
J. H. Pedersen-Lane, R. B. Zurier, and D. A. Lawrence
Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients
J. Leukoc. Biol., April 1, 2007; 81(4): 934 - 941.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
T. Thum, S. Hoeber, S. Froese, I. Klink, D. O. Stichtenoth, P. Galuppo, M. Jakob, D. Tsikas, S. D. Anker, P. A. Poole-Wilson, et al.
Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1
Circ. Res., February 16, 2007; 100(3): 434 - 443.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
T. Minamino and I. Komuro
Vascular Cell Senescence: Contribution to Atherosclerosis
Circ. Res., January 5, 2007; 100(1): 15 - 26.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
J. J. Fuster and V. Andres
Telomere Biology and Cardiovascular Disease
Circ. Res., November 24, 2006; 99(11): 1167 - 1180.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
X. Zhang, J. Kim, R. Ruthazer, M. A. McDevitt, D. E. Wazer, K. E. Paulson, and A. S. Yee
The HBP1 Transcriptional Repressor Participates in RAS-Induced Premature Senescence
Mol. Cell. Biol., November 15, 2006; 26(22): 8252 - 8266.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
V. W. Wen, K. Wu, S. Baksh, R. A. Hinshelwood, R. B. Lock, S. J. Clark, M. A.S. Moore, and K. L. MacKenzie
Telomere-Driven Karyotypic Complexity Concurs with p16INK4a Inactivation in TP53-Competent Immortal Endothelial Cells.
Cancer Res., November 15, 2006; 66(22): 10691 - 10700.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
T. Hayashi, H. Matsui-Hirai, A. Miyazaki-Akita, A. Fukatsu, J. Funami, Q.-F. Ding, S. Kamalanathan, Y. Hattori, L. J. Ignarro, and A. Iguchi
Endothelial cellular senescence is inhibited by nitric oxide: Implications in atherosclerosis associated with menopause and diabetes
PNAS, November 7, 2006; 103(45): 17018 - 17023.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
J. Chen and M. S. Goligorsky
Premature senescence of endothelial cells: Methusaleh's dilemma
Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1729 - H1739.
[Abstract] [Full Text] [PDF]


Home page
J. Am. Soc. Nephrol.Home page
M. E.J. Reinders, T. J. Rabelink, and D. M. Briscoe
Angiogenesis and Endothelial Cell Repair in Renal Disease and Allograft Rejection
J. Am. Soc. Nephrol., April 1, 2006; 17(4): 932 - 942.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
M. D. Edo and V. Andres
Aging, telomeres, and atherosclerosis
Cardiovasc Res, May 1, 2005; 66(2): 213 - 221.
[Abstract] [Full Text] [PDF]




© The Company of Biologists Ltd 2004