CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction.
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.
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Kentaro
K
Jujo
Hiromichi
H
Hamada
Atsushi
A
Iwakura
Tina
T
Thorne
Haruki
H
Sekiguchi
Trevor
T
Clarke
Aiko
A
Ito
Sol
S
Misener
Toshikazu
T
Tanaka
Ekaterina
E
Klyachko
Koichi
K
Kobayashi
Jörn
J
Tongers
Jérôme
J
Roncalli
Yukio
Y
Tsurumi
Nobuhisa
N
Hagiwara
Douglas W
DW
Losordo
D000818:Animals; D001483:Base Sequence; D001596:Benzylamines; D001772:Blood Cell Count; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D000080027:Cyclams; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001596:Benzylamines; C514936:CXCR4 protein, mouse; D000080027:Cyclams; D017931:DNA Primers; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9; C088327:plerixafor