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 (IR) 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 IR injury. Three days later, histological measurements of the infarct-area/area-at-risk ratio 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 7days in AMD3100-treated mice compared to just 1 day in the saline-treated mice. AMD3100 upregulated BM levels of endothelial nitric oxide synthase (eNOS) and two 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 IR injury, and these benefits appear to occur through a previously unidentified link between AMD3100 and BM eNOS expression.

CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice

“…In fact, treatment with AMD3100 after hepatic I/R injury resulted in mobilization of a previously described vasculogenic cell population (15). These findings are consistent with recent reports of improved tissue recovery with CXCR4 antagonism after injury in cardiac tissue, lung parenchyma, and skeletal muscle (14,23,34). The proposed mechanism for these findings is mobilization of endothelial progenitor cells and resultant improved angiogenesis in the recovery of ischemic tissue (25).…”

“…Previous studies suggested that SDF-1/CXCR4 signaling contributes to tissue recovery (8,14,35). We evaluated liver recovery after hepatic ischemia and 72, 96, and 168 h of reperfusion.…”

“Second-generation” stem cells for cardiac repair

“…Other acellular approaches have tried to promote stem cell recruitment by the infarcted myocardium. Modulation of the CXCchemokine receptor 4 and SDF-1 axis via gene therapy has shown to exert beneficial effects in preclinical studies and in human phase Ⅰ trials [164,165] . In spite of that, molecular, cellular and myocardial tissue regeneration mechanisms are highly complex and driven by the interplay of several factors, not yet completely understood.…”

Physiology and Pharmacology of Plerixafor

“…Transfer of PBMC mobilized with a combination of G-CSF plus plerixafor also resulted in an improvement in blood flow. Treatment with plerixafor was shown to reduce fibrosis and improve myocardial function and vascularity in a mouse model of myocardial infarction induced by ligation of the left ascending coronary artery [78] and after ischemia/reperfusion injury [80]. This was associated with mobilization of bone marrow-derived endothelial progenitor cells.…”