Paracrine Regulation of Cardiac miRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction
Background—Cell therapy with bone marrow-derived mononuclear cells (BMC) can improve recovery of cardiac function after 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.
Methods and Results—We demonstrated that intramyocardial delivery of BMC in infarcted mice regulates the expression of cardiac miRNAs and significantly down-regulates the pro-apoptotic miR-34a. In vitro studies confirmed that the supernatant of BMC inhibited the expression of H2O2-induced miR-34a and cardiomyocytes apoptosis. These effects were blocked by neutralizing antibodies directed against insulin growth factor-1 (IGF-1). Indeed, IGF-1 significantly inhibited H2O2-induced miR-34a expression, and miR-34a overexpression abolished the anti-apoptotic effect of IGF-1. Likewise, inhibition of IGF-1 signaling in vivo abolished the BMC-mediated inhibition of miR-34 expression and the protective effect on cardiac function and increased apoptosis and cardiac fibrosis. IGF-1 specifically blocked the expression of the precursor and the mature miR-34a, but did not interfere with the transcription of the primary miR-34a demonstrating that IGF-1 blocks the processing of miR-34a.
Conclusions—Together, our data demonstrate that the paracrine regulation of cardiac miRNAs by transplanted BMC contributes to the protective effects of cell therapy. BMC release IGF-1, which inhibits the processing of miR-34a, thereby blocking cardiomyocyte apoptosis.
- Received November 10, 2011.
- Accepted February 29, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited