Anti-Apoptotic Effect of Human Telomerase Reverse Transcriptase on Endothelial Cells under Oxidative Stress, Independent of Telomere Elongation and Telomerase Activity

Author(s): Iwao Kida, Motokuni Aoki, Toshio Ogihara, Hiromi Rakugi.

Journal Name: Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued)

Volume 13 , Issue 2 , 2013

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Abstract:

Increasing age and replicative senescence with critical shortening of telomeres is associated with endothelial dysfunction followed by atherosclerosis. Although human telomerase reverse transcriptase (hTERT) is suggested to play an important role in endothelial cells, the precise effect of hTERT is still uncertain. In this study we investigated telomerase- independent hTERT function against oxidative stress using a primary culture of endothelial cells in which telomerase enzymatic activity was inhibited by addition of 3’-azido-3’-deoxythymidine (AZT). Overexpression of hTERT attenuated H2O2-induced endothelial apoptosis, assessed by cell viability assay and flow cytometry, accompanied by significant reduction of caspase-3 activity. Of importance, it was suggested that this effect was independent of telomerase enzymatic activity because hTERT expression did not alter telomere length under addition of AZT. Also, suppression of human telomerase-associated protein 1 (TEP-1) by introduction of TEP-1-specific small interfering RNA (siRNA) did not affect the anti-apoptotic effect of hTERT, suggesting that hTERT does not cooperate with TEP-1, another component of telomerase. Moreover, the anti-apoptotic effect of hTERT was through attenuation of H2O2-induced upregulation of p53, followed by reduction of Bax and induction of Bcl-xL. Also, overexpression of hTERT resulted in activation of the transcription factor, NFκB, which is an anti-apoptotic factor. Altogether, the present study demonstrated the anti-apoptotic effect of not telomerase but hTERT itself on cultured endothelial cells under oxidative stress, independent of telomere elongation, followed by acquired replicative ability. Also, this function of hTERT did not require another protein component of telomerase. Moreover, the anti-apoptotic effect of hTERT on endothelial cells was mediated by two pathways; reduction of p53/Bax and activation of NFκB.

Keywords: Apoptosis, atherosclerosis, AZT, Bax, Bcl-xL, caspase-3, endothelial cell, hTERT, NFκB, oxidative stress, p53, telomerase, telomere length, TEP-1.

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Article Details

VOLUME: 13
ISSUE: 2
Year: 2013
Page: [112 - 121]
Pages: 10
DOI: 10.2174/1871522211313020005
Price: $58

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