Abstract 13019: Bone Marrow Mononuclear Cell-Derived IGF-1 Inhibits Processing of the Pro-Apoptotic miR-34a
Background: Cell therapy is a promising option for treatment of cardiovascular diseases. Cell therapy with bone marrow-derived mononuclear cells (BMC) can improve recovery of cardiac function after myocardial ischemia, however, the molecular mechanisms are not yet fully understood. MicroRNAs (miRNAs) are key regulators of gene expression and modulate the pathophysiology of cardiovascular diseases. In this study, we investigate whether intramyocardial delivery of BMC in infarcted mice regulates the expression of cardiac miRNAs following myocardial infarction in mice.
Method and Results: In vivo studies showed that intramyocardial delivery of BMC in myocardial infarction mice regulated the expression of cardiac miRNAs, in particular, significantly down-regulated the pro-apoptotic miR-34a (50.4±10.0% at day 7 compared to PBS treated mice, n=10-11; P<0.05). Additionally, in vitro studies confirmed that the supernatant of BMC significantly inhibited the expression of miR-34a and H2O2-induced cardiomyocyte apoptosis (n=9-13; P<0.05). These effects were blocked by neutralizing antibodies directed against the insulin growth factor-1 (IGF-1) (n=9-12; P<0.05). Vice versa, recombinant IGF-1 protein significantly inhibited H2O2-induced miR-34a up-regulation (28.1%±5.8 inhibition, n=11-12; P<0.05). Furthermore, inhibition of IGF-1 signaling in vivo abolished the protective effect of BMC on cardiac function and increased apoptosis and cardiac fibrosis (apoptosis;2.1±0.5-fold, fibrosis;1.9±0.2-fold increase, n=6-12; P<0.05). IGF-1 specifically blocked the expression of the precursor and the mature miR-34a (n=14; P<0.05), but did not interfere with the transcription of the primary miR-34a demonstrating that IGF-1 blocks the processing of miR-34a.
Conclusion: Our data demonstrate that the paracrine regulation of cardiac miRNAs by transplantated BMC contributes to the protective effects of cell therapy. BMC release IGF-1, which inhibits the processing of miR-34a thereby blocking cardiomyocytes apoptosis.
- © 2011 by American Heart Association, Inc.