Abstract 13971: Early Up-regulation of Myocardial Cxcr4 Expression is Critical for Cardiac Improvement With Chemical Preconditioning in Acute Myocardial Infarction
Introduction: We have demonstrated the importance of the stromal cell-derived factor (SDF):CXCR4 axis in myocardial repair. Prolonged expression of SDF-1 to a time when cardiac myocytes and cardiac stem cells express CXCR4 (CM-CXCR4) has been shown to significantly improve cardiac repair and function. In this study we tested the hypothesis that early up-regulation of CM-CXCR4 at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair.
Methods: The effects of the preconditioning agent - HIF hydroxylase inhibitor Dimethyloxalylglycine (DMOG) (1mM) on CXCR4 expression was tested in H9C2 cells in both normoxic and hypoxic conditions. Acute myocardial infarction (AMI) via left anterior descending (LAD) coronary artery ligation was induced on 8 week old CM-CXCR4 null and WT mice. Mice were randomly selected to receive injection of 5mg DMOG (DMOG group) or saline (Saline group) into the border zone immediately after LAD ligation. Serial echocardiography was used to assess cardiac function. Protein and mRNA expression of CM-CXCR4 were quantified by western blot, immunofluorescent staining, and qPCR.
Results: In the presence of hypoxia, DMOG (1mM) treatment upregulated CXCR4 expression of H9C2 cells by 29% and 42% at 15 and 24 hours, respectively. We observed no CM-CXCR4 expression in Saline group (both WT and CM-CXCR4 null mice) 15 hours post AMI. DMOG treatment induced CM-CXCR4 expression at 15 hours post AMI in WT mice but not in CM-CXCR4 null mice. The delivery DMOG led to a significant improvement in ejection fraction in WT (62%) mice (P=0.02) but not in CM-CXCR4 null mice (14%) 21days after AMI. Consistent with greater cardiac myocyte survival with ischemic preconditioning, we observed a significant increase in cardiac myosin-positive area within the infarct zone (36.5%) after DMOG treatment in WT mice, but no increase in CM-CXCR4 null mice.
Conclusion: Preconditioning with DMOG requires CM-CXCR4. These data suggest that engagement of the SDF-1:CXCR4 axis through the early up-regulation of CM-CXCR4 is a strategy for improving cardiac repair after AMI.
- © 2013 by American Heart Association, Inc.