Abstract 1957: GATA Transcription Factors Contribute to Endothelial Progenitor Cell Dysfunction in Patients With Coronary Artery Disease
Transplantation of bone-marrow derived endothelial progenitor cells (EPC) after myocardial infarction (MI) may improve myocardial healing and remodeling. However, progenitor cells from patients with coronary artery disease (CAD) display reduced proliferative and migratory capacity and thus autologous transplantation of EPC post MI often has little effects on neovascularisation and heart function. We screened dysfunctional EPC from patients with CAD (n=8) and healthy controls (n=7) by global transcriptome and realtime-PCR analysis. The transcription factors GATA2 and GATA3 were significantly repressed in EPC from CAD patients. Small interference RNA (siRNA) mediated functional knockdown of GATA2 or GATA3 impaired migratory capacity to 32%±7% and 61%±12% (p<0.05). Likewise, incorporation of EPC into vascular networks and endothelial tube formation on Matrigel plugs was completely inhibited by GATA2 and partly by GATA3 silencing. Colony forming capacity of EPC was also significantly reduced upon GATA2/3 knockdown. GATA2/3 silencing in cultured EPC attenuated the production of several cytokines such as the proangiogenic interleukin -8 (to 50% of control; p<0.05), stem cell factor-1 (to 20% of control; p<0.05) and hepatocyte growth factor (to 50% of controls, p<0.05). By combination of global transcriptome analysis and chromatin immunoprecipitation procedures we identified a set of important GATA target genes in EPC involved in migration, adhesion and proliferation. Finally, adenoviral overexpression of GATA transcription factors in dysfunctional EPC from patients with CAD normalized derailed target gene expression and resulted in improved EPC function. Targeting GATA transcription factors in dysfunctional EPC may improve neovascularisation and cardiac function after cell transplantation to ischemic tissues to prevent development of heart failure.