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Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells
OBJECTIVE—: Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversel...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965929/ https://www.ncbi.nlm.nih.gov/pubmed/29599138 http://dx.doi.org/10.1161/ATVBAHA.117.309940 |
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author | Richardson, Gavin David Sage, Andrew Bennaceur, Karim Al Zhrany, Nayef Coelho-Lima, Jose Dookun, Emily Draganova, Lilia Saretzki, Gabriele Breault, David T. Mallat, Ziad Spyridopoulos, Ioakim |
author_facet | Richardson, Gavin David Sage, Andrew Bennaceur, Karim Al Zhrany, Nayef Coelho-Lima, Jose Dookun, Emily Draganova, Lilia Saretzki, Gabriele Breault, David T. Mallat, Ziad Spyridopoulos, Ioakim |
author_sort | Richardson, Gavin David |
collection | PubMed |
description | OBJECTIVE—: Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence, a potential causative role of telomerase in atherogenesis is critically debated. APPROACH AND RESULTS—: In this study, we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures, we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4(+) cells and significantly reduced CD4(+) T-cell proliferation. The latter was telomerase dependent because oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase knockout mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase deficiency had no effect on regulatory T-cell (T(reg)) numbers in vivo or suppressive function ex vivo. Adoptive transfer of telomerase reverse transcriptase(–)(/–) T(regs) into Rag2(–/–) ApoE(–/–) (recombination activating gene 2/apolipoprotein E) double knockout mice demonstrated that telomerase function was not required for the ability of T(regs) to protect against atherosclerosis. However, telomere length was critical for T(reg) function. CONCLUSIONS—: Telomerase contributes to lymphocyte proliferation but plays no major role in T(reg) function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in T(regs). |
format | Online Article Text |
id | pubmed-5965929 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-59659292018-06-01 Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells Richardson, Gavin David Sage, Andrew Bennaceur, Karim Al Zhrany, Nayef Coelho-Lima, Jose Dookun, Emily Draganova, Lilia Saretzki, Gabriele Breault, David T. Mallat, Ziad Spyridopoulos, Ioakim Arterioscler Thromb Vasc Biol Basic Sciences OBJECTIVE—: Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence, a potential causative role of telomerase in atherogenesis is critically debated. APPROACH AND RESULTS—: In this study, we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures, we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4(+) cells and significantly reduced CD4(+) T-cell proliferation. The latter was telomerase dependent because oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase knockout mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase deficiency had no effect on regulatory T-cell (T(reg)) numbers in vivo or suppressive function ex vivo. Adoptive transfer of telomerase reverse transcriptase(–)(/–) T(regs) into Rag2(–/–) ApoE(–/–) (recombination activating gene 2/apolipoprotein E) double knockout mice demonstrated that telomerase function was not required for the ability of T(regs) to protect against atherosclerosis. However, telomere length was critical for T(reg) function. CONCLUSIONS—: Telomerase contributes to lymphocyte proliferation but plays no major role in T(reg) function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in T(regs). Lippincott Williams & Wilkins 2018-06 2018-05-29 /pmc/articles/PMC5965929/ /pubmed/29599138 http://dx.doi.org/10.1161/ATVBAHA.117.309940 Text en © 2018 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. |
spellingShingle | Basic Sciences Richardson, Gavin David Sage, Andrew Bennaceur, Karim Al Zhrany, Nayef Coelho-Lima, Jose Dookun, Emily Draganova, Lilia Saretzki, Gabriele Breault, David T. Mallat, Ziad Spyridopoulos, Ioakim Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells |
title | Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells |
title_full | Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells |
title_fullStr | Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells |
title_full_unstemmed | Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells |
title_short | Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells |
title_sort | telomerase mediates lymphocyte proliferation but not the atherosclerosis-suppressive potential of regulatory t-cells |
topic | Basic Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965929/ https://www.ncbi.nlm.nih.gov/pubmed/29599138 http://dx.doi.org/10.1161/ATVBAHA.117.309940 |
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