Abstract 1475: Small molecule CXCR4 Antagonist Augments Mobilization and Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells into Sites of Myocardial Neovascularization and Reduces Mortality After Myocardial Infarction
Background: The SDF-1a/CXCR4 axis plays key regulatory roles in the trafficking and movement of human CD34+ cells to bone marrow (BM). We hypothesized that AMD3100, a CXCR4 antagonist, could augment mobilization and incorporation of BM-derived endothelial progenitor cells (EPCs) into sites of myocardial neovascularization in the setting of myocardial infarction (MI) and thereby enhance functional recovery.
Methods and Results: One hr after induction of MI, WT mice received either AMD3100 (125ug, single subcutaneous injection) or saline. FACS analysis disclosed a significant increase in Sca-1/Flk-1 double-positive cells in AMD vs. control mice at one hour and 7 days after MI (p<0.05 vs. control). Histological and functional assessment revealed increased capillary density, a decreased ratio of fibrosis to left ventricular (LV) area, and better LV function in the AMD group four weeks after MI, resulting in improved survival of the AMD treated mice (p<0.05). In MI models using mice transplanted with BM from Tie-2-Lac Z mice, more abundant X-gal positive cells were recruited to the ischemic areas in the AMD group one and two weeks after MI (P<0.05) and more recruited cells were double-pos for β-gal and isolectin B4 in the AMD group, indicating an increase in bone marrow derived cells incorporated into the myocardial microvasculature. QRT-PCR study of BM and peripheral blood (PB) mononuclear cells (MNCs) from WT mice with MI +/− AMD treatment revealed that AMD worked as a CXCR4 antagonist for 1 day after injection, however, it significantly increased CXCR4 and MMP-9 mRNA expression 7 days after MI compared with control(p<0.05). SDF-1 in injured myoc was upregulated at 3 and 7 days after MI (P=0.01 vs. uninjured) and AMD did not affect the SDF-1 upregulation. In MMP-9 deficient mice, beneficial effects by AMD on MI, including reduced fibrosis and increased capillary density in the infarct zone, were attenuated.
Conclusions: The CXCR4 antagonist AMD3100, despite is short plasma half-life, exerts delayed effects on gene expression resulting in late mobilization of BM derived cells, and preserved LV function after MI. Ongoing studies are aiming to define the pathway(s) of gene regulation to better understand the therapeutic effect of this small molecule CXCR4 antagonist.