CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism

Kentaro Jujo, Masaaki Ii*, Haruki Sekiguchi, Ekaterina Klyachko, Sol Misener, Toshikazu Tanaka, Jörn Tongers, Jérôme Roncalli, Marie Ange Renault, Tina Thorne, Aiko Ito, Trevor Clarke, Christine Kamide, Yukio Tsurumi, Nobuhisa Hagiwara, Gangjian Qin, Michio Asahi, Douglas W. Losordo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)63-73
Number of pages11
JournalCirculation
Volume127
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • ischemia
  • myocardium
  • nitric oxide synthase
  • pharmaceutical preparations
  • reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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