Abstract 3667: Single Dose CXCR4 Antagonist Enhances Recovery From Ischemia Reperfusion Injury While Continuous Blockade Abolishes Treatment Effect
Background: Prior studies in our lab indicated that AMD3100 enhanced recovery in the setting of myocardial infarction following permanent coronary ligation, however no data exists regarding the effect of this therapy in the more clinically relevant setting of ischemia reperfusion (IR). Accordingly we performed a series of experiments to evaluate the effect of AMD3100 on mobilization and incorporation of BM-derived endothelial progenitor cells (EPCs) into sites of myocardial neovascularization following IR.
Methods and Results: Immediately after the induction of IR injury (60 min-LAD occlusion followed by reperfusion), 10 –12 week-old C57BL6/J wild-type mice were randomized to receive either a single subcutaneous injection of AMD3100 (5 mg/kg), continuous AMD infusion via osmotic pump (total of 2.5 mg/mouse for 7 days) or saline. Analysis of mobilization of BM-derived EPCs, assessed by a validated culture assay technique, showed a significant increase in both AMD groups 3 days after IR (43.3±12.2; 45.5±18.3 vs. 32.3±9.1 cells/HPF Saline-group, p<0.05). Histological and functional assessments revealed increased capillary density (188.7±52.5 vs. 113.5±13.4 cells/HPF, p<0.05), decreased fibrosis area (27.6±10.9 vs. 43.3±17.0%, p<0.05), and better LV function (Day28 LVFS: 38.3±6.1 vs. 28.0±5.0%, p<0.05) in the single AMD group 4 weeks after IR. On the contrary, continuous AMD treatment did not result in improved histological or functional outcome after IR (all p=NS). In addition to animal experiments, analysis of 7-day cultured EPCs from BM-mononuclear cells showed in vitro that AMD treatment resulted in significant induction of migration, adhesion and proliferation of EPCs (all p<0.05). These results suggest that AMD has a direct effect on BM EPCs to activate functionally, and enhances EPC mobilization into circulation after ischemic insult.
Conclusions: The CXCR4 antagonist AMD3100 augmented mobilization of BM-derived EPCs into sites of neovascularization, resulting in preservation of LV function after IR. These cardioprotective effects of AMD3100 mediate CXCR4 expression on BM EPCs.