Downregulation of ETS rescues diabetes-induced reduction of endothelial progenitor cells

PLoS One. 2009;4(2):e4529. doi: 10.1371/journal.pone.0004529. Epub 2009 Feb 19.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow
  • DNA-Binding Proteins / analysis
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology*
  • Down-Regulation / genetics*
  • Endothelial Cells / pathology
  • Humans
  • Matrix Metalloproteinase 9
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / pathology*
  • Mice
  • Proto-Oncogene Protein c-ets-1 / genetics
  • Proto-Oncogene Proteins c-ets / genetics*
  • RNA, Small Interfering / pharmacology
  • Receptor, Macrophage Colony-Stimulating Factor
  • Signal Transduction
  • Stem Cells / pathology
  • Transcriptional Activation

Substances

  • DNA-Binding Proteins
  • Ets1 protein, mouse
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins c-ets
  • RNA, Small Interfering
  • Receptor, Macrophage Colony-Stimulating Factor
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse