Abstract
Background: Recent studies have been shown that CXCR4 antagonist AMD3100 rapidly mobilizes stem/progenitor cells from BM and prior studies suggested a potential therapeutic effect in MI. This study was performed to explore the mechanisms of this effect in a mouse ischemia reperfusion (IR) injury model. Methods and Results: 8- to 12-week-old wild-type (WT) mice were treated with single sc injections of either AMD3100 (5 mg/kg) or saline immediately after IR injury (60 min-LAD occlusion followed by reperfusion). FACS analyses identified a significant increase in the number of circulating EPCs(culture method; Day7: 76.0±23.9 vs 34.6±6.1 cells/uL PB, p <0.05) in AMD-treated mice on days 3–7 after IR, and ELISA indicated that AMD increased levels of MMP-9 and soluble Kit ligand in BM(Day 3 MMP-9: 88.6±12.7 vs 53.9±24.5 ug/mL, p <0.05; sKitL: 20.4±3.3 vs 13.0±4.1 vs. pg/mL, p <0.05). On day 3 after IR histo analyses revealed a lower ratio of infarct area/area at risk (AAR) (15.8±2.2% vs 31.9±9.4, p <0.05) in AMD-treated mice. On day 28 AMD-treated mice had greater capillary density in AAR (188.7±52.5 vs 113.5±13.4/HPF, p <0.05) and less fibrosis(27.6±10.9 vs 43.3±17.0%, p <0.05). 4 wks after IR, echocardiograpy showed better LV function in AMD-treated mice (Day28 LVFS: 38.3±6.1% vs. 28.0±5.0, p <0.05). To determine whether favorable effect of AMD on recovery after IR is dependent on CXCR4 expression on BM cells, we induced IR injury in WT mice transplanted with BM from CXCR4 conditional KO donor mice. In BM-transplanted mice, AMD continued to increase EPC mobilization from BM after IR, as well as increasing levels of MMP-9 and sKit ligand in BM(all p<.05). However, the enhanced cardiac functional recovery observed in mice with WT BM was lost in mice with CXCR4 null BM . These results indicate that the EPC mobilizing effect of AMD is CXCR4 independent, while the BM CXCR4 is essential for AMD mediated preservation of cardiac function after IR. Conclusions: This study provides novel mechanistic insights into the cardioprotective effects of CXCR4 antagonist AMD3100 indicating that MMP-9 and Kit ligand contribute to AMD-induced EPC mobilization independent of CXCR4 but that the receptor is essential for AMD mediated myocardial protection.
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