Research Paper Volume 13, Issue 17 pp 21364—21384
Deferoxamine accelerates endothelial progenitor cell senescence and compromises angiogenesis
- 1 Cardiovascular Center, Department of Internal Medicine, And Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan
- 2 Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan
- 3 Institute of Biomedical Sciences, MacKay Medical College, New Taipei 25245, Taiwan
Received: February 19, 2021 Accepted: August 2, 2021 Published: September 11, 2021https://doi.org/10.18632/aging.203469
How to Cite
Copyright: © 2021 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Senescence reduces the circulating number and angiogenic activity of endothelial progenitor cells (EPCs), and is associated with aging-related vascular diseases. However, it is very time-consuming to obtain aged cells (~1 month of repeated replication) or animals (~2 years) for senescence studies. Here, we established an accelerated senescence model by treating EPCs with deferoxamine (DFO), an FDA-approved iron chelator. Four days of low-dose (3 μM) DFO induced senescent phenotypes in EPCs, including a senescent pattern of protein expression, impaired mitochondrial bioenergetics, altered mitochondrial protein levels and compromised angiogenic activity. DFO-treated early EPCs from young and old donors (< 35 vs. > 70 years old) displayed similar senescent phenotypes, including elevated senescence-associated β-galactosidase activity and reduced relative telomere lengths, colony-forming units and adenosine triphosphate levels. To validate this accelerated senescence model in vivo, we intraperitoneally injected Sprague-Dawley rats with DFO for 4 weeks. Early EPCs from DFO-treated rats displayed profoundly senescent phenotypes compared to those from control rats. Additionally, in hind-limb ischemic mice, DFO pretreatment compromised EPC angiogenesis by reducing both blood perfusion and capillary density. DFO thus accelerates EPC senescence and appears to hasten model development for cellular senescence studies.
CFU: colony-forming unit; CSIG: cell senescence-inhibited gene; DFO: deferoxamine; Drp1: dynamin-related protein 1; eNOS: endothelial nitric-oxide synthase; EPC: endothelial progenitor cell; Fis1: mitochondrial fission 1 protein; MFN1: mitofusin-1; MTP18: mitochondrial protein 18 kDa; OCR: oxygen consumption rate; plasminogen activator inhibitor-1: PAI-1; Sirt1: sirtuin (silent mating type information regulation 2 homolog) 1; SA-βGal: senescence-associated β-galactosidase; Skp2: S phase-associated protein-2.