CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction
| Autor: | Douglas W. Losordo, Koichi Kobayashi, Aiko Ito, Yukio Tsurumi, Atsushi Iwakura, Kentaro Jujo, Jérôme Roncalli, Jörn Tongers, Tina Thorne, Ekaterina Klyachko, Trevor Clarke, Hiromichi Hamada, Toshikazu Tanaka, Nobuhisa Hagiwara, Haruki Sekiguchi, Sol Misener |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Cardiac function curve
Male Vascular Endothelial Growth Factor A Benzylamines Receptors CXCR4 genetic structures Myocardial Infarction Neovascularization Physiologic Mice Transgenic Cyclams Neovascularization Mice Fibrosis Heterocyclic Compounds Medicine Animals Myocardial infarction Progenitor cell Hematopoietic Stem Cell Mobilization Bone Marrow Transplantation DNA Primers Mice Knockout Multidisciplinary Base Sequence business.industry Endothelial Cells Biological Sciences medicine.disease Hematopoietic Stem Cells eye diseases Blood Cell Count Capillaries Mice Inbred C57BL Vascular endothelial growth factor A medicine.anatomical_structure Matrix Metalloproteinase 9 Immunology Cancer research cardiovascular system Female Bone marrow sense organs medicine.symptom business |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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