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Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells
BACKGROUND: Transplantation of vasculogenic progenitor cells (VPC) improves neovascularization after ischemia. However, patients with type 2 diabetes mellitus show a reduced VPC number and impaired functional activity. Previously, we demonstrated that p38 kinase inhibition prevents the negative effe...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639694/ https://www.ncbi.nlm.nih.gov/pubmed/19225563 http://dx.doi.org/10.1371/journal.pone.0004529 |
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author | Seeger, Florian Hartmut Chen, Linping Spyridopoulos, Ioakim Altschmied, Joachim Aicher, Alexandra Haendeler, Judith |
author_facet | Seeger, Florian Hartmut Chen, Linping Spyridopoulos, Ioakim Altschmied, Joachim Aicher, Alexandra Haendeler, Judith |
author_sort | Seeger, Florian Hartmut |
collection | PubMed |
description | BACKGROUND: Transplantation of vasculogenic progenitor cells (VPC) improves neovascularization after ischemia. However, patients with type 2 diabetes mellitus show a reduced VPC number and impaired functional activity. Previously, we demonstrated that p38 kinase inhibition prevents the negative effects of glucose on VPC number by increasing proliferation and differentiation towards the endothelial lineage in vitro. Moreover, the functional capacity of progenitor cells is reduced in a mouse model of metabolic syndrome including type 2 diabetes (Lepr(db)) in vivo. FINDINGS: The aim of this study was to elucidate the underlying signalling mechanisms in vitro and in vivo. Therefore, we performed DNA-protein binding arrays in the bone marrow of mice with metabolic syndrome, in blood-derived progenitor cells of diabetic patients as well as in VPC ex vivo treated with high levels of glucose. The transcriptional activation of ETS transcription factors was increased in all samples analyzed. Downregulation of ETS1 expression by siRNA abrogated the reduction of VPC number induced by high-glucose treatment. In addition, we observed a concomitant suppression of the non-endothelial ETS-target genes matrix metalloproteinase 9 (MMP9) and CD115 upon short term lentiviral delivery of ETS-specific shRNAs. Long term inhibition of ETS expression by lentiviral infection increased the number of cells with the endothelial markers CD144 and CD105. CONCLUSION: These data demonstrate that diabetes leads to dysregulated activation of ETS, which blocks the functional activity of progenitor cells and their commitment towards the endothelial cell lineage. |
format | Text |
id | pubmed-2639694 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-26396942009-02-19 Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells Seeger, Florian Hartmut Chen, Linping Spyridopoulos, Ioakim Altschmied, Joachim Aicher, Alexandra Haendeler, Judith PLoS One Research Article BACKGROUND: Transplantation of vasculogenic progenitor cells (VPC) improves neovascularization after ischemia. However, patients with type 2 diabetes mellitus show a reduced VPC number and impaired functional activity. Previously, we demonstrated that p38 kinase inhibition prevents the negative effects of glucose on VPC number by increasing proliferation and differentiation towards the endothelial lineage in vitro. Moreover, the functional capacity of progenitor cells is reduced in a mouse model of metabolic syndrome including type 2 diabetes (Lepr(db)) in vivo. FINDINGS: The aim of this study was to elucidate the underlying signalling mechanisms in vitro and in vivo. Therefore, we performed DNA-protein binding arrays in the bone marrow of mice with metabolic syndrome, in blood-derived progenitor cells of diabetic patients as well as in VPC ex vivo treated with high levels of glucose. The transcriptional activation of ETS transcription factors was increased in all samples analyzed. Downregulation of ETS1 expression by siRNA abrogated the reduction of VPC number induced by high-glucose treatment. In addition, we observed a concomitant suppression of the non-endothelial ETS-target genes matrix metalloproteinase 9 (MMP9) and CD115 upon short term lentiviral delivery of ETS-specific shRNAs. Long term inhibition of ETS expression by lentiviral infection increased the number of cells with the endothelial markers CD144 and CD105. CONCLUSION: These data demonstrate that diabetes leads to dysregulated activation of ETS, which blocks the functional activity of progenitor cells and their commitment towards the endothelial cell lineage. Public Library of Science 2009-02-19 /pmc/articles/PMC2639694/ /pubmed/19225563 http://dx.doi.org/10.1371/journal.pone.0004529 Text en Seeger et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Seeger, Florian Hartmut Chen, Linping Spyridopoulos, Ioakim Altschmied, Joachim Aicher, Alexandra Haendeler, Judith Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells |
title | Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells |
title_full | Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells |
title_fullStr | Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells |
title_full_unstemmed | Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells |
title_short | Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells |
title_sort | downregulation of ets rescues diabetes-induced reduction of endothelial progenitor cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639694/ https://www.ncbi.nlm.nih.gov/pubmed/19225563 http://dx.doi.org/10.1371/journal.pone.0004529 |
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