Abstract 19872: Overexpression of MicroRNA-130a in Developing Cardiomyocytes Results in Ventricular Wall Hypoplasia
Introduction: Cardiac development is a complex process regulated in part by the combinatorial interactions of multiple transcriptional regulators requiring strict control of temporal-spatial expression. MicroRNAs (miRNAs) are small RNA molecules capable of mediating this fine control by binding to mRNA targets and inhibiting message translation. MiRNAs interact with mRNA through sequence specific interactions; however, there remains varying degrees of complementarity along the sequence allowing one miRNA to interact with several genes. We have previously reported on the identification of Friend of Gata-2 (FOG-2) as a target of miRNA-130a. We hypothesized that this miRNA targets multiple genes important for cardiac development.
Results: We generated transgenic mice with cardiomyocyte specific overexpression of miRNA-130a during cardiac development using the βMHC promoter. Overepxression of microRNA-130a was embryonic lethal by day 15.5. At embryonic day 14.5, transgenic embryos were found to have reduced fractional shortening (24% vs. 50%, p< 0.0001), increased left ventricular end-diastolic diameter (1.15 mm vs. 0.79 mm, p< 0.0001), and lower heart rate (192.6 bpm vs 129.4 bpm, p=0.0015). Analysis of transgenic embryos revealed ventricular wall hypoplasia of both right and left and right ventricles, each approximately 2-4 cells thick compared to 15-18 cells in controls. Also present were ventricular septal defects and a reduction in the number of epicardial vessels. Using the computational programs TargetScanS and EIMMo, we identified several predicted targets of miRNA-130a representing key biological processes including angiogenesis, cell proliferation, and cation transport. With our transgenic model, we found that, in addition to FOG-2, several predicted targets of miRNA-130a show reduced protein levels including: transforming growth factor beta receptor 2 (TGFβR2), mesenchyme homeobox 2 (MEOX2), and connexin 43. These genes are known to play important roles in proper coronary vasculature formation or cardiomyocyte proliferation.
Conclusion: MicroRNA-130a is a key regulator of cardiac development and coronary vessel formation through the regulation of several genes including FOG-2, MEOX2, Connexin43, and TGFβR2.
- © 2010 by American Heart Association, Inc.