Abstract 13486: MicroRNA-378 Targets IGF1 Receptor and Regulates Cardiomyocyte Survival
During post-natal maturation, progressive withdrawal of cardiac myocytes from the cell cycle is characterized by a marked decrease in the insulin-like growth factor 1 (IGF1) and IGF1-receptor (IGF1R) expression, but the underlying mechanism remains unexplored. MicroRNAs are a class of non-coding RNAs that have emerged as important regulators of many aspects of development, homeostasis, and disease. In this study, we hypothesized the role of microRNAs in post-natal cardiac remodeling. In mice, by real-time PCR, we observed a 10- fold increase in the cardiac expression level of miR-378 following 7 days of birth as compared to 16th day fetus. Expression of miR-378 was also found induced by 2-fold in the aged (12 month) vs the young (1 month) heart. Tissue distribution analysis showed high abundance of miR-378 in the heart and its specific expression in cardiac myocytes but not in cardiac fibroblasts. We also observed induction of miR-378 expression in cardiomyocytes by a variety of stressors such as low glucose, H2O2, high doses of phenylephrine and campothecin. In addition, cardiac expression of miR-378 is found inversely related to the expression of IGF-1 and IGF1R after birth. We observed the presence of a highly conserved miR-378 binding sequence in the 3’UTR of IGF1R. Ectopic expression of miR-378 by its mimic in cardiomyocytes, was found to repress IGF-1 and IGF-1R protein levels and attenuated IGF1-induced Akt signaling, in a dose dependent manner. It also enhanced H2O2 induced caspase activity, and DNA fragmentation as assessed by TUNEL staining. The knock-down of miR-378 by its antagomiR on the other hand, enhanced IGF1R expression and protected cardiomyocytes against H2O2 induced damage. In addition, our data indicate that the ligand IGF1 is a repressor of miR-378. Indeed high expression of IGF1 correlated with the absence of miR-378 in cardiac fibroblasts and low levels of miR-378 in the fetal heart, and vice versa after birth. Together, our findings identify miR-378 abundance and myocyte specific expression in the heart, and unravel a unique reciprocal molecular circuit between miR-378, IGF1R and IGF-1, a circuit that is tightly linked to the post-natal cardiac remodeling and cardiomyocyte survival during aging.
- © 2011 by American Heart Association, Inc.