Abstract 15339: Bone marrow Mononuclear Cell Therapy Regulates the Expression of Pro-apoptotic and Pro-fibrotic MiRNAs in the Infarcted Heart
Background: Cell-based therapy is a promising option for treatment of cardiovascular diseases. Bone marrow-derived mononuclear cells (BMCs) administration showed beneficial effects after acute myocardial infarction (MI). However, the molecular mechanisms are not yet fully understood. MicroRNAs (miRs) are key regulators of gene expression that control mRNA degradation and translation and modulate the pathophysiology of cardiovascular diseases. In this study, we investigated whether administration of BMCs regulated cardiac miRs after induction of MI in mice.
Methods and Results: We first performed miR microarray analysis using RNA isolated of the border zone of the heart of mice with MI, which were treated with BMCs or PBS. The treatment with BMCs down-regulated the pro-fibrotic miR-21 (38.1±11.2% at day 7 compared to PBS treated mice) and significantly down-regulated the pro-apoptotic miR-34a (50.4±10.0% at day 7 compared to PBS treated mice). These data were confirmed by qPCR (n=11; p<0.05). Recent studies demonstrated that miR-34a promoted apoptosis of tumor cells and we confirmed the pro-apoptotic activity of miR-34a in cultured cardiac myocytes (induction of apoptosis by miR-34a:1.46 folds; inhibition of miR-34a: 29.3±12.9% reduction; both p<0.05). Furthermore, inhibition of miR-34a by antagomirs treatment in vivo significantly reduced cardiomyocyte apoptosis after MI (61.2±10.3% inhibition). To determine the underlying mechanism, we tested the effect of BMCs-supernatant on the expression of miR-34a in cultured cardiomyocytes. Indeed, BMCs-supernatant reduced H2O2-induced up-regulation of miR-34a. Furthermore, we demonstrated that insulin-like growth factor -1 (IGF-1) and hepatocyte growth factor (HGF), which are released by BMCs, prevented H2O2-induced up-regulation of miR-34a in vitro. Neutralizing antibodies directed against IGF-1 and HGF prevented the anti-apoptotic activity mediated by BMCs-supernatants.
Conclusion: Administration of BMCs prevents the increased expression of pro-fibrotic and pro-apoptotic miRs in the infarct border zone. In particular, the reduction of the pro-apoptotic miR-34a may be mediated by the release of IGF-1 and HGF from BMCs and contribute to the beneficial effect of cell therapy of MI.
- © 2010 by American Heart Association, Inc.