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 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 (Leprdb) 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.

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Metadaten
Author:Florian Hartmut Seeger, Linping Chen, Ioakim Spyridopoulos, Joachim Altschmied, Alexandra Aicher, Judith Haendeler
URN:urn:nbn:de:hebis:30-68217
DOI:https://doi.org/10.1371/journal.pone.0004529
ISSN:1932-6203
Parent Title (English):PLoS One
Document Type:Article
Language:English
Date of Publication (online):2009/02/19
Date of first Publication:2009/02/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2009/08/11
Volume:4
Issue:(2): e4529
Note:
Copyright: © 2009 Seeger et al. 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 credited.
Source:PLoS ONE 4(2): e4529. ; doi:10.1371/journal.pone.0004529
HeBIS-PPN:214820505
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 3.0