Abstract 17977: Mir-133 Transfection in Mscs Downregulates Critical Pro-Apoptotic Genes in the Infarct Heart and Improves Cardiac Function
Cell-based therapy (cardiomyoplasty) is one of the most promising techniques for repair and regeneration of the infarcted myocardium. Mesenchymal stem cells (MSCs) are pluripotent, adult stem cells that are easily expanded in culture, and can differentiate into numerous lineages, including vascular endothelial cells and cardiomyocytes. Unfortunately, a major impediment to the improvement of cardiac function following stem cell transplantation has been survival of the cells in the infarct myocardium due to the severely hypoxic nature of this tissue. The lack of oxygen and nutrients ultimately leads to apoptosis of the majority of the transplanted stem cells, thereby limiting engraftment and the chance of favorable outcome. microRNAs (miRNAs) are major post-transcriptional regulatory molecules that mainly suppress protein translation through binding their 3’UTR. microRNA-133a (miR-133a) is highly downregulated in hypertrophy and congestive heart failure in patients and in our animal model of myocardial infarction (MI). We found that transfecting MSCs with miR-133a decreases hypoxia-reoxygenation (6h of hypoxia, 12h reoxygenation) induced cell death and improves survival of MSCs. Similarly, transplantation of miR-133a transfected MSCs in rat (Fisher-344) hearts subjected to myocardial infarction (MI) by temporarily ligating the left coronary artery (LAD) and release, there was a significant improvement in cardiac function and decreased fibrosis when compared with MSC or MI groups. In addition, we performed a 96-well PCR array for apoptosis-related genes. The results from PCR array showed a 3-fold downregulation of ABL1 (c-abl oncogene 1, non-receptor tyrosine kinase) and BFAR (Bifunctional apoptosis regulator genes) in miR-133+MSCs as compared with the untreated MI group. This study demonstrated for the first time that the combination of miR-133a mimics along with MSCs improves cardiac function, decreases fibrosis and pro-apoptotic ABL1 and BFAR genes in the infarcted heart.
- Cardiovascular disease prevention
- Coronary artery disease
- Heart failure
- Ischemia reperfusion
- © 2011 by American Heart Association, Inc.