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

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posted on 19.11.2013, 00:00 authored by Ivana Knezevic, Aalok Patel, Nagalingam R. Sundaresan, Mahesh P. Gupta, R. John Solaro, Raghu S. Nagalingam, Madhu Gupta
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.


The study was supported by NIH-Multi P.I. grant 2RO1 HL 22231 (MG and RJS), NIH PO1 HL 062626-Project 1 (RJS), NIH RO1 HL 83423 (MPG) and NIH T32 HL 07692 (IK).


Publisher Statement

This research was originally published in Journal of Biological Chemistry. Knezevic, I. Patel, A. Sundaresan, N. R. Gupta, M. P. Solaro, R. J. Nagalingam, R. S. Gupta, M. A novel cardiomyocyte enriched microRNA, miR-378, targets IGF1R: implications in post natal cardiac remodeling and cell survival. Journal of Biological Chemistry. 2012. Apr 13;287(16):12913-26. © the American Society for Biochemistry and Molecular Biology


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