Abstract 5371: Bone Marrow MMP-9 Expression Mediates Therapeutic Effect of Selective CXCR4 Antagonist AMD3100 on Myocardial Infarction
Background: SDF-1a/CXCR4 axis plays a key role in trafficking and movement of bone marrow (BM) cells. We hypothesized that AMD3100, a CXCR4 antagonist, could augment mobilization and recruitment of BM-derived endothelial progenitor cells (EPCs) into sites of ischemia following myocardial infarction (MI) and thereby enhance the cardiac functional recovery.
Methods and Results: Wild type (WT) mice received either AMD (5mg/kg, single subcutaneous injection) or saline (control) immediately after MI induction. BM-derived EPC mobilization (EPC-MB) assessed by FACS analysis with Sca-1/Flk-1 markers disclosed a significant increase in the AMD-treated mice 7 days after MI. Cardiac function was evaluated by echo and histology 4 weeks after MI. LV function was significantly preserved with increased vascularity and decreased fibrosis leading to improved survival rate following MI in the AMD group. We then examined BM-derived EPC contribution to ischemic myocardium using a Tie2/LacZ-BM transplantation (BMT) mouse MI model. XGal staining revealed an increase in b-gal expressing cells (i.e. BM derived, Tie-2 positive) in the AMD group, suggesting that AMD not only promoted EPC-MB but also enhanced EPC recruitment to sites of neovascularization. Next, we performed a series of in vitro/vivo experiments to explore the mechanism for EPC-MB by AMD. One of the metalloproteases MMP-9 but not MMP-2 mRNA expression was significantly upregulated in the AMD-treated bone marrow mononuclear cells (BMMNC). In vivo, no therapeutic effect of AMD on MI was observed in MMP9 KO mice. Moreover, in BMT mouse MI studies: MMP-9 KO mice with WT BM (MMP9-WTBM) and WT mice with MMP-9 KO BM (WT-MMP9BM), the MMP9-WTBM group exhibited favorable effects of AMD on MI with increased EPC-MB but the WT-MMP9BM exhibited no EPC-MB, suggesting that BM MMP-9 expression was necessary for CXCR4 antagonism-dependent EPC-MB and recruitment to ischemic myocardium by AMD.
Conclusions: Single administration of CXCR4 antagonist AMD, despite its short half-life in plasma, exerts delayed effects on EPC-MB via MMP-9 expression resulting in preserved LV function after MI. Our data provide novel mechanistic insights into the therapeutic effect of AMD3100 in MI.