downregulation of ets rescues diabetes-induced reduction of endothelial progenitor cellsdownregulation ets的救援diabetes-induced减少内皮祖细胞.pdfVIP

Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells 1 1 1 2 Florian Hartmut Seeger , Linping Chen , Ioakim Spyridopoulos , Joachim Altschmied , Alexandra Aicher1, Judith Haendeler1,2¤* ¨ 1 Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany, 2 Cell Biology Molecular Aging Research, IUF (Institut fur Umweltmedizinische Forschung) at the University of Duesseldorf gGmbH, Duesseldorf, Germany 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 (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 in