title: A novel cardiomyocyte-enriched microRNA, miR-378, targets insulin-like growth factor 1 receptor: implications in postnatal cardiac remodeling and cell survival.
abstract: Postnatal 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 postnatal cardiac remodeling. By expression profiling, we observed a 10-fold increase in miR-378 expression in 1-week-old neonatal mouse hearts compared with 16-day-old fetal hearts. There was also a 4-6-fold induction in expression of miR-378 in older (10 months) compared with younger (1 month) hearts. Interestingly, tissue distribution analysis identified miR-378 to be highly abundant in heart and skeletal muscles. In the heart, specific expression was observed in cardiac myocytes, which was inducible by a variety of stressors. Overexpression 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 anti-miR protected cardiomyocytes against H(2)O(2) 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 cardioabundant microRNA that targets IGF1R. We also demonstrate the existence of a negative feedback loop between miR-378, IGF1R, and IGF1 that is associated with postnatal cardiac remodeling and with the regulation of cardiomyocyte survival during stress.
authors.affiliation: Department of Physiology and Biophysics, and Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Knezevic
authors.forename: Aalok
authors.initials: A
authors.lastname: Patel
authors.forename: Nagalingam R
authors.initials: NR
authors.lastname: Sundaresan
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: Raghu S
authors.initials: RS
authors.lastname: Nagalingam
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006321:Heart / Q000254:growth & development / Q000502:physiology*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: C546119:MIRN378 microRNA, mouse; C572773:MIRN378 microRNA, rat; D035683:MicroRNAs; D017526:Receptor, IGF Type 1; C514862:Akt1 protein, mouse; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt