Abstract 16226: Deferoxamine Accelerates Senescence in Endothelial Progenitor Cells (EPC) in vitro and in vivo - A Promising Model for EPC Senescence Research
Background: EPC senescence leads to circulating EPC number reduction, which is closely related to aging-related vascular diseases. However, researches on EPC senescence are always very time-consuming in obtaining aged cells (~ 1 month by repeated replication) or animals (~2 years). We sought to establish an accelerating senescence model of EPC by the treatment with deferoxamine (DFO), an iron chelator.
Methods & Results: Four days of low-dose DFO (3 μM) treatment in human late EPCs resulted in accelerating senescence completely mirroring replication-induced senescent phenotypes, including senescent markers (increased senescence-associated β-galactosidase [SA-βGal] activity and p53 expression, decreased Sirt1, Skp2, and cell senescence-inhibited gene [CSIG] expression), mitochondrial bioenergetics and dynamics (reduced real-time oxygen consumption rates and ATP production, reduced mitochondrial fission protein Fis1 and MTP18 expression), and functional profiles (reduced cell proliferative and migratory capacity, enhanced PAI-1 but reduced eNOS expression). Furthermore, early EPCs from young donors (<35 years) treated with DFO demonstrated increased SA-βGal activities, decreased relative telomere lengths, reduced colony-forming units (CFUs) and ATP production, a senescent picture perfectly consistent with that of early EPCs isolated from old donors (>70 years). To further confirm this model in vivo, SD rats or C57/BL6 mice underwent daily intraperitoneal injection of DFO (5 or 50 mg/kg/day) for 4 weeks. Compared with control (saline) group, early EPC from DFO-treated animals had significantly higher levels of SA-βGal activities, and lower levels of ATP production and CFUs. In line with this data, DFO-treated animals also had significantly delayed perfusion recovery after hind-limb ischemia induced by femoral arterial cessation. Lastly, many putative anti-aging substances were screened using this model. Among them, resveratrol and salvianolic acid B were found to partially but significantly reverse DFO-induced EPC senescence.
Conclusions: DFO treatment may help establish an accelerating EPC senescence model in vitro and in vivo that may enable previously very time-consuming EPC senescence studies to be expedited.
- © 2013 by American Heart Association, Inc.