title: MiR-378 controls cardiac hypertrophy by combined repression of mitogen-activated protein kinase pathway factors.
abstract: BACKGROUND
  Several microRNAs (miRs) have been shown to regulate gene expression in the heart, and dysregulation of their expression has been linked to cardiac disease. miR-378 is strongly expressed in the mammalian heart but so far has been studied predominantly in cancer, in which it regulates cell survival and tumor growth.
  
  
  RESULTS
  Here, we report tight control of cardiomyocyte hypertrophy through miR-378. In isolated primary cardiomyocytes, miR-378 was found to be both necessary and sufficient to repress cardiomyocyte hypertrophy. Bioinformatic prediction suggested that factors of the mitogen-activated protein kinase (MAPK) pathway are enriched among miR-378 targets. Using mRNA and protein expression analysis along with luciferase assays, we validated 4 key components of the MAPK pathway as targets of miR-378: MAPK1 itself, insulin-like growth factor receptor 1, growth factor receptor-bound protein 2, and kinase suppressor of ras 1. RNA interference with these targets prevented the prohypertrophic effect of antimiR-378, suggesting their functional relation with miR-378. Because miR-378 significantly decreases in cardiac disease, we sought to compensate for its loss through adeno-associated virus-mediated, cardiomyocyte-targeted expression of miR-378 in an in vivo model of cardiac hypertrophy (pressure overload by thoracic aortic constriction). Restoration of miR-378 levels significantly attenuated thoracic aortic constriction-induced cardiac hypertrophy and improved cardiac function.
  
  
  CONCLUSIONS
  Our data identify miR-378 as a regulator of cardiomyocyte hypertrophy, which exerts its activity by suppressing the MAPK signaling pathway on several distinct levels. Restoration of disease-associated loss of miR-378 through cardiomyocyte-targeted adeno-associated virus-miR-378 may prove to be an effective therapeutic strategy in myocardial disease.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Technische Universität München, Munich, Germany.
authors.forename: Jayavarshni
authors.initials: J
authors.lastname: Ganesan
authors.forename: Deepak
authors.initials: D
authors.lastname: Ramanujam
authors.forename: Yassine
authors.initials: Y
authors.lastname: Sassi
authors.forename: Andrea
authors.initials: A
authors.lastname: Ahles
authors.forename: Claudia
authors.initials: C
authors.lastname: Jentzsch
authors.forename: Stanislas
authors.initials: S
authors.lastname: Werfel
authors.forename: Simon
authors.initials: S
authors.lastname: Leierseder
authors.forename: Xavier
authors.initials: X
authors.lastname: Loyer
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.forename: Bernhard
authors.initials: B
authors.lastname: Laggerbauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051380:GRB2 Adaptor Protein; C572773:MIRN378 microRNA, rat; D035683:MicroRNAs; D017451:Receptors, Somatomedin; D011494:Protein Kinases; C097199:KSR-1 protein kinase; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: cardiomyocytes; gene therapy; hypertrophy; microRNA