Abstract 17659: Novel Role for Bioactive Lipids in Mobilization of Bone Marrow Stem Cells During Myocardial Ischemia: Sphingosine-1 Phosphate (S1P) as Potential Therapeutic Target
Background: Acute myocardial infarction (AMI) triggers mobilization of BM-derived stem cells (BMSCs) through poorly understood processes. Recently we have postulated a major role for bioactive lipids (BAL) such as sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) in mobilization of BMSCs into peripheral blood (PB). We hypothesized that manipulating S1P levels after AMI could augment BMSC mobilization and enhance cardiac function after AMI.
Methods: AMI was induced by ligating the left anterior descending artery (LAD) in GFP BM chimera mice. S1P manipulation was achieved by treating infarcted mice with SPL inhibitor tetrahydroxybutylimidazole (THI) at a dose of 25 mg/L + 10 g/L glucose in drinking water for 4 days (commencing at day 4 after AMI onset). PB samples were obtained before and after AMI at different time intervals and were examined for BAL using mass spectrometry and circulating BMSCs using flow cytometry. Cardiac function was assessed using echocardiography before AMI and after 48 and 4 weeks after AMI.
Results: Plasma BAL peaked at 5 days after AMI and declined to near baseline levels within 10 days (P < 0.05 for 5 days vs. baseline). Elevated plasma bioactive lipids were paralleled by significant increase in circulating lineage negative (Lin-)/Sca1+/cKit+ (P < 0.01 vs. controls). We observed greater than 2-fold upregulation in plasma levels of BAL with THI supplementation which was positively correlated with significant upregulation in BMSC mobilization (Fig. 1). Mice treated with THI demonstrated better recovery of cardiac functional parameters as assessed by echocardiography. THI treatment led to significantly higher rates of GFP+ cells in the myocardium at 2 weeks after MI and BrdU+ cells at 2 and 4 weeks after AMI.
Conclusion: This data suggests that pharmacologically elevated plasma bioactive lipids contribute to BMSC mobilization and may represent an attractive strategy for enhancing myocardial recovery and improved BMSC targeting.
- © 2013 by American Heart Association, Inc.