title: The miR-19a/b family positively regulates cardiomyocyte hypertrophy by targeting atrogin-1 and MuRF-1.
abstract: Progressive cardiac hypertrophy owing to pathological stimuli, such as pressure overload, is frequently associated with the development of heart failure, a major cause of morbidity and mortality worldwide. Growing evidence has shown that miRNAs are extensively involved in the pathogenesis of cardiac hypertrophy. In the present study, we examined the hypothesis that the miR-19a/b family acts as a key regulator of cardiac hypertrophy and apoptosis. Forced overexpression of miR-19a/b was sufficient to induce hypertrophy in rat neonatal cardiomyocytes. Luciferase assays revealed that miR-19a/b directly target the anti-hypertrophic genes atrogin-1 and MuRF-1 (muscle RING-finger protein-1). The endogenous expressions of the target genes were down-regulated by miR-19a/b. Pro-hypertrophic calcineurin/NFAT (nuclear factor of activated T-cells) signalling was elevated markedly in the presence of miR-19b, and the calcineurin inhibitor CsA (cyclosporin A) and the PKC (protein kinase C) inhibitor GF10923X significantly attenuated the miR-19b-mediated increase in cell size and expression of hypertrophic markers. Furthermore, miR-19b led to increased cell survival through up-regulation of the NFAT target gene encoding α-crystallin-B and repression of the pro-apoptotic gene Bim (Bcl-2-interacting mediator of cell death) under ER (endoplasmic reticulum) stress conditions. Taken together, the results of the present study demonstrate that the miR-19a/b family regulates phenotypes of cardiomyocytes via suppression of multiple direct target genes.
authors.affiliation: *School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Song
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Ryu
authors.forename: Jin Ock
authors.initials: JO
authors.lastname: Kim
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Kwon
authors.forename: Do Han
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018390:Gene Targeting; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D005810:Multigene Family / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C586754:MIRN19 microRNA, rat; D035683:MicroRNAs; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases