A novel cardiomyocyte enriched microRNA, miR-378, targets IGF1R: implications in post natal cardiac remodeling and cell survival

Post-natal cardiac remodeling is characterized by a marked decrease in the insulin-like growth factor 1 (IGF1) and IGF1-receptor (IGF1R) expression. The underlying mechanism remains unexplored. This study examined the role of microRNAs in post-natal cardiac remodeling. By expression profiling, we observed a 10- fold increase in miR-378 expression in 1 wk old neonatal mouse hearts compared to 16th day old fetal hearts. There was also a 4 to 6-fold induction in expression of miR-378 in older (10 month) compared to younger (1 month) hearts. Interestingly, tissue distribution analysis identified miR-378 to be highly abundant in heart and skeletal muscle. In the heart, specific expression was observed in cardiac myocytes, which was inducible by a variety of stressors. Over-expression of miR-378 enhanced apoptosis of cardiomyocytes by direct targeting of IGF1R and reduced signaling in Akt cascade. The inhibition of miR-378 by its antimiR protected cardiomyocytes against H2O2 and hypoxia-reoxygenation induced cell-death by promoting IGF1R expression and downstream Akt-signaling cascade. Additionally, our data show that miR-378 expression is inhibited by IGF1 in cardiomyocytes. In tissues such as fibroblasts and fetal hearts, where IGF1 levels are high, we found either absent or significantly low miR-378 levels, suggesting an inverse relationship between these two factors. Our study identifies miR-378 as a new cardio-abundant microRNA which targets IGF1R. We also demonstrate the existence of a negative feedback loop between miR-378, IGF1R and IGF1 that is associated with post-natal cardiac remodeling and with the regulation of cardiomyocyte survival during stress.