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lüll CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism Jujo K; Ii M; Sekiguchi H; Klyachko E; Misener S; Tanaka T; Tongers J; Roncalli J; Renault MA; Thorne T; Ito A; Clarke T; Kamide C; Tsurumi Y; Hagiwara N; Qin G; Asahi M; Losordo DWCirculation 2013[Jan]; 127 (1): 63-73BACKGROUND: CXC-chemokine receptor 4 (CXCR4) regulates the retention of stem/progenitor cells in the bone marrow (BM), and the CXCR4 antagonist AMD3100 improves recovery from coronary ligation injury by mobilizing stem/progenitor cells from the BM to the peripheral blood. Thus, we investigated whether AMD3100 also improves recovery from ischemia/reperfusion injury, which more closely mimics myocardial infarction in patients, because blood flow is only temporarily obstructed. METHODS AND RESULTS: Mice were treated with single subcutaneous injections of AMD3100 (5 mg/kg) or saline after ischemia/reperfusion injury. Three days later, histological measurements of the ratio of infarct area to area at risk were smaller in AMD3100-treated mice than in mice administered saline, and echocardiographic measurements of left ventricular function were greater in the AMD3100-treated mice at week 4. CXCR4(+) cells were mobilized for just 1 day in both groups, but the mobilization of sca1(+)/flk1(+) cells endured for 7 days in AMD3100-treated mice compared with just 1 day in the saline-treated mice. AMD3100 upregulated BM levels of endothelial nitric oxide synthase (eNOS) and 2 targets of eNOS signaling, matrix metalloproteinase-9 and soluble Kit ligand. Furthermore, the loss of BM eNOS expression abolished the benefit of AMD3100 on sca1(+)/flk1(+) cell mobilization without altering the mobilization of CXCR4(+) cells, and the cardioprotective effects of AMD3100 were retained in eNOS-knockout mice that had been transplanted with BM from wild-type mice but not in wild-type mice with eNOS-knockout BM. CONCLUSIONS: AMD3100 prolongs BM progenitor mobilization and improves recovery from ischemia/reperfusion injury, and these benefits appear to occur through a previously unidentified link between AMD3100 and BM eNOS expression.|Animals[MESH]|Benzylamines[MESH]|Bone Marrow Transplantation[MESH]|Cardiotonic Agents/pharmacology[MESH]|Cyclams[MESH]|Disease Models, Animal[MESH]|Female[MESH]|Gene Expression Regulation, Enzymologic/drug effects[MESH]|Hematopoietic Stem Cell Mobilization/methods[MESH]|Hematopoietic Stem Cells/cytology/drug effects/physiology[MESH]|Heterocyclic Compounds/*pharmacology[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Myocardial Infarction/drug therapy/metabolism[MESH]|Myocardial Reperfusion Injury/*drug therapy/*metabolism[MESH]|Nitric Oxide Synthase Type III/genetics/*metabolism[MESH]|Receptors, CXCR4/*antagonists & inhibitors[MESH]|Recovery of Function/drug effects[MESH]|Signal Transduction/drug effects[MESH] |