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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:e54.)
© 2003 American Heart Association, Inc.

Letters to the Editor

Research Letter

Role of Telomerase in Human Endothelial Cell Proliferation

David J. Kurz

Cardiovascular Research, Institute of Physiology, University of Zurich, and Cardiology, University Hospital, Zurich, Switzerland

Jorge D. Erusalimsky

The Cell Biology Group at the British Heart Foundation Laboratories, Department of Medicine, University College London, London, UK

To the Editor:

Conflicting views exist as to whether human endothelial cells express telomerase^1–4 and, if they do, to what extent telomerase fulfills a physiological function. This may be due to the fact that activity levels in endothelial cells are low compared with tumor cells,⁴ and that during serial passage, endothelial cell telomeres continually shorten, in apparent defiance of the established function of telomerase, namely telomere length maintenance. In our own study published recently in this Journal,⁴ we demonstrated that telomerase activity is reversibly upregulated in proliferating endothelial cells but is not detectable during quiescence. We further showed that telomerase was upregulated by fibroblast growth factor-2 (FGF-2) but not by vascular endothelial growth factor A (VEGF), an effect that was associated with an extended replicative life span during serial passage of endothelial cells in the presence of FGF-2 compared with VEGF. It was noteworthy that this could not be attributed to a decrease in the rate of telomere shortening. To explain this phenomenon, we proposed that in human endothelial cells telomerase plays an active role in promoting extended cell growth by a mechanism that preserves telomere function independently of telomere length maintenance.

Substantial evidence has now been published to support this model of telomerase function in somatic human cells. In a study investigating the relationship between telomerase and telomere structure and function in normal human fibroblasts, Masutomi et al⁵ demonstrated the presence of telomerase in these cells. They further showed that although levels of expression were extremely low, they prevented premature senescence of fibroblasts. In agreement with our observations in endothelial cells, they also showed that inhibition of telomerase expression had no effect on the rate of telomere erosion. In contrast, these low levels of telomerase were associated with the maintenance of the short terminal stretch of single-stranded telomeric DNA known as the 3' overhang. According to this model, the single-stranded overhang contributes to telomere stability by folding back into the double-stranded region of the telomere to form the so-called T-loop, a structure which is further stabilized by a complex array of telomere-binding proteins.⁶ Current evidence suggests that this supramolecular assembly provides a capping mechanism that prevents telomeres from being recognized as a double-stranded break. The finding that, at least in organisms with short telomeres (eg, humans), low levels of telomerase activity are involved in preserving this structure endorses the previously suggested contention that it is the integrity of the telomere, rather than its overall length, that is essential for the maintenance of telomere function and replicative capacity.⁷ This modified model of telomerase function in normal human cells is consistent with earlier work demonstrating that endothelial cells ectopically expressing high levels of telomerase escape senescence despite the fact that their telomere length continued to decrease to a level far below that of normal senescent cells.²

Finally, the work of Masutomi et al⁵ may have important implications with regard to potential toxic effects of telomerase-inhibiting drugs. Clinical trials to assess the value of these compounds as anticancer agents are currently being planned, and potential strategies include long-term maintenance therapy of patients in clinical remission. In view of the newly discovered physiological role of telomerase in somatic cells, one might envisage a number of vascular side effects resulting from such therapies, including atherothrombotic events after loss of endothelial integrity or loss of atherosclerotic plaque stability and impaired formation of collaterals to ischemic tissues.

References

1. Hsaio R, Sharma HW, Ramakrishnan S, Keith E, Narayanan R. Telomerase activity in normal human endothelial cells. Anticancer Res. 1997; 17: 827–832.[Medline] [Order article via Infotrieve]
2. Yang J, Chang E, Cherry AM, Bangs CD, Oei Y, Bodnar A, Bronstein A, Chiu CP, Herron GC. Human endothelial cell life expansion by telomerase expression. J Biol Chem. 1999; 274: 26141–26148.[Abstract/Free Full Text]
3. Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res. 2000; 87: 540–542.[Free Full Text]
4. Kurz DJ, Hong Y, Trivier E, Huang HL, Decary S, Hong Zang G, Lüscher TF, Erusalimsky JD. Fibroblast growth factor-2, but not vascular endothelial growth factor, up-regulates telomerase activity in human endothelial cells. Arterioscler Thromb Vasc Biol. 2003; 23: 748–754.[Abstract/Free Full Text]
5. Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC. Telomerase maintains telomere structure in normal human cells. Cell. 2003; 114: 241–253.[CrossRef][Medline] [Order article via Infotrieve]
6. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T. Mammalian telomeres end in a large duplex loop. Cell. 1999; 97: 503–514.[CrossRef][Medline] [Order article via Infotrieve]
7. Blackburn EH. Switching and signaling at the telomere. Cell. 2001; 106: 661–673.[CrossRef][Medline] [Order article via Infotrieve]

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