CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction
Open Access
- 15 June 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (24), 11008-11013
- https://doi.org/10.1073/pnas.0914248107
Abstract
We hypothesized that a small molecule CXCR4 antagonist, AMD3100 (AMD), could augment the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs), thereby enhancing neovascularization and functional recovery after myocardial infarction. Single-dose AMD injection administered after the onset of myocardial infarction increased circulating EPC counts and myocardial vascularity, reduced fibrosis, and improved cardiac function and survival. In mice transplanted with traceable BM cells, AMD increased BM-derived cell incorporation in the ischemic border zone. In contrast, continuous infusion of AMD, although increasing EPCs in the circulation, worsened outcome by blocking EPC incorporation. In addition to its effects as a CXCR4 antagonist, AMD also up-regulated VEGF and matrix metalloproteinase 9 (MMP-9) expression, and the benefits of AMD were not observed in the absence of MMP-9 expression in the BM. These findings suggest that AMD3100 preserves cardiac function after myocardial infarction by enhancing BM-EPC–mediated neovascularization, and that these benefits require MMP-9 expression in the BM, but not in the ischemic region. Our results indicate that AMD3100 could be a potentially useful therapy for the treatment of myocardial infarction.Keywords
This publication has 45 references indexed in Scilit:
- G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanismBlood, 2006
- VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularizationThe FASEB Journal, 2006
- Signals from the Sympathetic Nervous System Regulate Hematopoietic Stem Cell Egress from Bone MarrowCell, 2006
- Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9–mediated progenitor cell mobilizationThe Journal of Experimental Medicine, 2005
- The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF aloneBlood, 2005
- Current Status and Future Prospects for Acute Myocardial Infarction TherapyCirculation, 2003
- Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonistBlood, 2003
- Diabetes mellitus and acute myocardial infarction: more data supporting a poorer microvasculature reperfusionAmerican Heart Journal, 2003
- The α-Chemokine, Stromal Cell-derived Factor-1α, Binds to the Transmembrane G-protein-coupled CXCR-4 Receptor and Activates Multiple Signal Transduction PathwaysJournal of Biological Chemistry, 1998
- The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral BloodThe Journal of Experimental Medicine, 1997