© 2000 American Heart Association, Inc.
Reports |
Nitric Oxide Activates Telomerase and Delays Endothelial Cell Senescence
From Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Germany.
Correspondence to Stefanie Dimmeler, PhD, Molecular Cardiology, University of Frankfurt, Theodor Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler@em.uni-frankfurt.de
Key Words: nitric oxide • aging • endothelial cells • telomerase
 |
Introduction |
|---|
Endothelial cells (ECs) undergo a limited number of cell divisions, ultimately stop dividing, and enter a state that is designated replicative senescence. Shortening of telomeres is believed to be a molecular clock that triggers senescence. Telomerase, a RNA-directed DNA polymerase, extends telomeres of eukaryotic chromosomes and delays the development of senescence. In this study, we examined telomere length and the activity of telomerase during aging of human ECs in culture and elucidated the effect of nitric oxide (NO). A significant increase in senescent cells as detected by acidic ß-galactosidase expression and a reduction of telomere length were found after 11 passages. Telomerase activity was reduced after the seventh passage, thereby preceding the development of EC senescence. The repeated addition of the NO donor S-nitroso-penicillamine significantly reduced EC senescence and delayed age-dependent inhibition of telomerase activity, whereas inhibition of endogenous NO synthesis had an adverse effect. Taken together, our results demonstrate that telomerase inactivation precedes EC aging. NO prevents age-related downregulation of telomerase activity and delays EC senescence.
The incidence of atherosclerosis increases with age. Aging is associated not only with endothelial dysfunction, a key pathogenic factor in atherosclerotic disease progression,1 2 but also impairs angiogenesis,3 suggesting that the process of aging itself affects endothelial cell (EC) function.
On a cellular level, aging leads to an irreversible state of cell cycle
arrest known as replicative senescence.4 It is generally
believed that a relevant factor in regulating cellular life span is the
telomere length.5 Telomerase, a ribonucleoprotein with
reverse transcriptase activity, synthesizes
This article has been cited by other articles:
 |
|
 |
|
  R. Menghini, V. Casagrande, M. Cardellini, E. Martelli, A. Terrinoni, F. Amati, M. Vasa-Nicotera, A. Ippoliti, G. Novelli, G. Melino, et al. MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1 Circulation, October 13, 2009; 120(15): 1524 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Erusalimsky and C. Skene Mechanisms of endothelial senescence Exp Physiol, March 1, 2009; 94(3): 299 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Oeseburg, D. Iusuf, P. van der Harst, W. H. van Gilst, R. H. Henning, and A. J.M. Roks Bradykinin Protects Against Oxidative Stress-Induced Endothelial Cell Senescence Hypertension, February 1, 2009; 53(2): 417 - 422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Farsetti, A. Grasselli, S. Bacchetti, C. Gaetano, and M. C. Capogrossi The telomerase tale in vascular aging: regulation by estrogens and nitric oxide signaling J Appl Physiol, January 1, 2009; 106(1): 333 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Erusalimsky Vascular endothelial senescence: from mechanisms to pathophysiology J Appl Physiol, January 1, 2009; 106(1): 326 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jakob, P. Schroeder, M. Lukosz, N. Buchner, I. Spyridopoulos, J. Altschmied, and J. Haendeler Nuclear Protein Tyrosine Phosphatase Shp-2 Is One Important Negative Regulator of Nuclear Export of Telomerase Reverse Transcriptase J. Biol. Chem., November 28, 2008; 283(48): 33155 - 33161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 L. Zeng and Q. Xu eNOS-ER{alpha} Complex Goes to Telomerase Circ. Res., July 3, 2008; 103(1): 10 - 12. [Full Text] [PDF]
|
|
|
|
|
|
A. Grasselli, S. Nanni, C. Colussi, A. Aiello, V. Benvenuti, G. Ragone, F. Moretti, A. Sacchi, S. Bacchetti, C. Gaetano, et al. Estrogen Receptor-{alpha} and Endothelial Nitric Oxide Synthase Nuclear Complex Regulates Transcription of Human Telomerase Circ. Res., July 3, 2008; 103(1): 34 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Scalera, J. Martens-Lobenhoffer, A. Bukowska, U. Lendeckel, M. Tager, and S. M. Bode-Boger Effect of Telmisartan on Nitric Oxide-Asymmetrical Dimethylarginine System: Role of Angiotensin II Type 1 Receptor and Peroxisome Proliferator Activated Receptor {gamma} Signaling During Endothelial Aging Hypertension, March 1, 2008; 51(3): 696 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Minamino and I. Komuro Vascular Cell Senescence: Contribution to Atherosclerosis Circ. Res., January 5, 2007; 100(1): 15 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Fuster and V. Andres Telomere Biology and Cardiovascular Disease Circ. Res., November 24, 2006; 99(11): 1167 - 1180. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Doshida, M. Ohmichi, S. Tsutsumi, J. Kawagoe, T. Takahashi, B. Du, A. Mori-Abe, T. Ohta, M. Saitoh-Sekiguchi, K. Takahashi, et al. Raloxifene Increases Proliferation and Up-regulates Telomerase Activity in Human Umbilical Vein Endothelial Cells J. Biol. Chem., August 25, 2006; 281(34): 24270 - 24278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yokoi, K. Fukuo, O. Yasuda, M. Hotta, J. Miyazaki, Y. Takemura, H. Kawamoto, H. Ichijo, and T. Ogihara Apoptosis Signal-Regulating Kinase 1 Mediates Cellular Senescence Induced by High Glucose in Endothelial Cells Diabetes, June 1, 2006; 55(6): 1660 - 1665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Aviv, A. Valdes, J. P. Gardner, R. Swaminathan, M. Kimura, and T. D. Spector Menopause Modifies the Association of Leukocyte Telomere Length with Insulin Resistance and Inflammation J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 635 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M Bode-Boger, F. Scalera, and J. Martens-Lobenhoffer Asymmetric dimethylarginine (ADMA) accelerates cell senescence Vascular Medicine, July 1, 2005; 10(1_suppl): S65 - S71. [Abstract] [PDF]
|
|
|
|
|
|
S. M Bode-Boger, F. Scalera, and J. Martens-Lobenhoffer Asymmetric dimethylarginine (ADMA) accelerates cell senescence Vascular Medicine, May 1, 2005; 10(2_suppl): S65 - S71. [Abstract] [PDF]
|
|
|
|
 |
|
 M. D. Edo and V. Andres Aging, telomeres, and atherosclerosis Cardiovasc Res, May 1, 2005; 66(2): 213 - 221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Brandes, I. Fleming, and R. Busse Endothelial aging Cardiovasc Res, May 1, 2005; 66(2): 286 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Zaccagnini, C. Gaetano, L. Della Pietra, S. Nanni, A. Grasselli, A. Mangoni, R. Benvenuto, M. Fabrizi, S. Truffa, A. Germani, et al. Telomerase Mediates Vascular Endothelial Growth Factor-dependent Responsiveness in a Rat Model of Hind Limb Ischemia J. Biol. Chem., April 15, 2005; 280(15): 14790 - 14798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, A. Zacharek, C. Zhang, H. Jiang, Y. Li, C. Roberts, M. Lu, A. Kapke, and M. Chopp Endothelial Nitric Oxide Synthase Regulates Brain-Derived Neurotrophic Factor Expression and Neurogenesis after Stroke in Mice J. Neurosci., March 2, 2005; 25(9): 2366 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Murga, O. Fernandez-Capetillo, and G. Tosato Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2 Blood, March 1, 2005; 105(5): 1992 - 1999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Pascale, G. C. Reale, and E. D'Ambrosio Tumor Cells Fail to trans-Induce Telomerase in Human Umbilical Vein Endothelial Cell Cultures Cancer Res., November 1, 2004; 64(21): 7702 - 7705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Scalera, J. Borlak, B. Beckmann, J. Martens-Lobenhoffer, T. Thum, M. Tager, and S. M. Bode-Boger Endogenous Nitric Oxide Synthesis Inhibitor Asymmetric Dimethyl L-Arginine Accelerates Endothelial Cell Senescence Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1816 - 1822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Asahara and A. Kawamoto Endothelial progenitor cells for postnatal vasculogenesis Am J Physiol Cell Physiol, September 1, 2004; 287(3): C572 - C579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Kurz, S. Decary, Y. Hong, E. Trivier, A. Akhmedov, and J. D. Erusalimsky Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells J. Cell Sci., May 1, 2004; 117(11): 2417 - 2426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Haendeler, J. Hoffmann, J. F. Diehl, M. Vasa, I. Spyridopoulos, A. M. Zeiher, and S. Dimmeler Antioxidants Inhibit Nuclear Export of Telomerase Reverse Transcriptase and Delay Replicative Senescence of Endothelial Cells Circ. Res., April 2, 2004; 94(6): 768 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Serrano and V. Andres Telomeres and Cardiovascular Disease: Does Size Matter? Circ. Res., March 19, 2004; 94(5): 575 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Csiszar, Z. Ungvari, A. Koller, J. G. Edwards, and G. Kaley Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging Physiol Genomics, March 12, 2004; 17(1): 21 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Kurz and J. D. Erusalimsky Research Letter: Role of Telomerase in Human Endothelial Cell Proliferation Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): e54 - 54. [Full Text]
|
|
|
|
 |
|
 E. Sadoun and M. J. Reed Impaired Angiogenesis in Aging Is Associated with Alterations in Vessel Density, Matrix Composition, Inflammatory Response, and Growth Factor Expression J. Histochem. Cytochem., September 1, 2003; 51(9): 1119 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Haendeler, J. Hoffmann, R. P. Brandes, A. M. Zeiher, and S. Dimmeler Hydrogen Peroxide Triggers Nuclear Export of Telomerase Reverse Transcriptase via Src Kinase Family-Dependent Phosphorylation of Tyrosine 707 Mol. Cell. Biol., July 1, 2003; 23(13): 4598 - 4610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Dewberry, D. C. Crossman, and S. E. Francis Interleukin-1 Receptor Antagonist (IL-1RN) Genotype Modulates the Replicative Capacity of Human Endothelial Cells Circ. Res., June 27, 2003; 92(12): 1285 - 1287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Assmus, C. Urbich, A. Aicher, W. K. Hofmann, J. Haendeler, L. Rossig, I. Spyridopoulos, A. M. Zeiher, and S. Dimmeler HMG-CoA Reductase Inhibitors Reduce Senescence and Increase Proliferation of Endothelial Progenitor Cells via Regulation of Cell Cycle Regulatory Genes Circ. Res., May 16, 2003; 92(9): 1049 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Kurz, Y. Hong, E. Trivier, H.-L. Huang, S. Decary, G. H. Zang, T. F. Luscher, and J. D. Erusalimsky Fibroblast Growth Factor-2, But Not Vascular Endothelial Growth Factor, Upregulates Telomerase Activity in Human Endothelial Cells Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 748 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Deshpande, B. Qi, Y. C. Park, and K. Irani Constitutive Activation of rac1 Results in Mitochondrial Oxidative Stress and Induces Premature Endothelial Cell Senescence Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): e1 - 6. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Murasawa, J. Llevadot, M. Silver, J. M. Isner, D. W. Losordo, and T. Asahara Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells Circulation, August 27, 2002; 106(9): 1133 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Chen, S. V. Brodsky, D. M. Goligorsky, D. J. Hampel, H. Li, S. S. Gross, and M. S. Goligorsky Glycated Collagen I Induces Premature Senescence-Like Phenotypic Changes in Endothelial Cells Circ. Res., June 28, 2002; 90(12): 1290 - 1298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.M. Vanhoutte Ageing and endothelial dysfunction Eur. Heart J. Suppl., February 1, 2002; 4(suppl_A): A8 - A17. [Abstract] [PDF]
|
|
|
|
|
|
S. J. Zieman, G. Gerstenblith, E. G. Lakatta, G. O. Rosas, K. Vandegaer, K. M. Ricker, and J. M. Hare Upregulation of the Nitric Oxide-cGMP Pathway in Aged Myocardium : Physiological Response to l-Arginine Circ. Res., January 19, 2001; 88(1): 97 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hoffmann, J. Haendeler, A. Aicher, L. Rossig, M. Vasa, A. M. Zeiher, and S. Dimmeler Aging Enhances the Sensitivity of Endothelial Cells Toward Apoptotic Stimuli: Important Role of Nitric Oxide Circ. Res., October 12, 2001; 89(8): 709 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsushita, E. Chang, A. J. Glassford, J. P. Cooke, C.-P. Chiu, and P. S. Tsao eNOS Activity Is Reduced in Senescent Human Endothelial Cells: Preservation by hTERT Immortalization Circ. Res., October 26, 2001; 89(9): 793 - 798. [Abstract] [Full Text] [PDF]
|
|