title: CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Jujo
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Haruki
authors.initials: H
authors.lastname: Sekiguchi
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Klyachko
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Jörn
authors.initials: J
authors.lastname: Tongers
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roncalli
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Renault
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Aiko
authors.initials: A
authors.lastname: Ito
authors.forename: Trevor
authors.initials: T
authors.lastname: Clarke
authors.forename: Christine
authors.initials: C
authors.lastname: Kamide
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tsurumi
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Hagiwara
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.forename: Michio
authors.initials: M
authors.lastname: Asahi
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000818:Animals; D001596:Benzylamines; D016026:Bone Marrow Transplantation; D002316:Cardiotonic Agents / Q000494:pharmacology; D000080027:Cyclams; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001596:Benzylamines; D002316:Cardiotonic Agents; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C088327:plerixafor