title: Deficiency of cardiomyocyte-specific microRNA-378 contributes to the development of cardiac fibrosis involving a transforming growth factor β (TGFβ1)-dependent paracrine mechanism.
abstract: Understanding the regulation of cardiac fibrosis is critical for controlling adverse cardiac remodeling during heart failure. Previously we identified miR-378 as a cardiomyocyte-abundant miRNA down-regulated in several experimental models of cardiac hypertrophy and in patients with heart failure. To understand the consequence of miR-378 down-regulation during cardiac remodeling, our current study employed a locked nucleic acid-modified antimiR to target miR-378 in vivo. Results showed development of cardiomyocyte hypertrophy and fibrosis in mouse hearts. Mechanistically, miR-378 depletion was found to induce TGFβ1 expression in mouse hearts and in cultured cardiomyocytes. Among various secreted cytokines in the conditioned-media of miR-378-depleted cardiomyocytes, only TGFβ1 levels were found to be increased. The increase was prevented by miR-378 expression. Treatment of cardiac fibroblasts with the conditioned media of miR-378-depleted myocytes activated pSMAD2/3 and induced fibrotic gene expression. This effect was counteracted by including a TGFβ1-neutralizing antibody in the conditioned-medium. In cardiomyocytes, adenoviruses expressing dominant negative N-Ras or c-Jun prevented antimiR-mediated induction of TGFβ1 mRNA, documenting the importance of Ras and AP-1 signaling in this response. Our study demonstrates that reduction of miR-378 during pathological conditions contributes to cardiac remodeling by promoting paracrine release of profibrotic cytokine, TGFβ1 from cardiomyocytes. Our data imply that the presence in cardiomyocyte of miR-378 plays a critical role in the protection of neighboring fibroblasts from activation by pro-fibrotic stimuli.
authors.affiliation: Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612 and.
authors.forename: Raghu S
authors.initials: RS
authors.lastname: Nagalingam
authors.affiliation: Department of Cardiothoracic Surgery, University of Chicago, Chicago, Illinois 60637.
authors.forename: Nagalingam R
authors.initials: NR
authors.lastname: Sundaresan
authors.affiliation: Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612 and.
authors.forename: Mariam
authors.initials: M
authors.lastname: Noor
authors.affiliation: Department of Cardiothoracic Surgery, University of Chicago, Chicago, Illinois 60637.
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
authors.affiliation: Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612 and.
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.affiliation: Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois, Chicago, Illinois 60612 and. Electronic address: guptam@uic.edu.
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D004719:Endomyocardial Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C546119:MIRN378 microRNA, mouse; C572773:MIRN378 microRNA, rat; D035683:MicroRNAs; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C497787:Smad3 protein, rat; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D020559:Monomeric GTP-Binding Proteins; C586503:Nras protein, mouse
keywords: Cardiac Hypertrophy; Cardiomyocyte; Fibroblast; Gene Expression; Heart Failure; MicroRNA (miRNA); Transforming Growth Factor β (TGF-B)
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