title: miR-146a targets Fos expression in human cardiac cells.
abstract: miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-κB, a transcription factor induced by pro-inflammatory molecules (such as TNF-α) that is strongly related to the pathogenesis of cardiac disorders. The main goal of this study consisted of studying new roles of miR-146a in cardiac pathological processes caused by the pro-inflammatory cytokine TNF-α. Our results demonstrate that miR-146a transcript levels were sharply increased in cardiac ventricular tissue of transgenic mice with specific overexpression of TNF-α in the heart, and also in a cardiomyocyte cell line of human origin (AC16) exposed to TNF-α. Among all the in silico predicted miR-146a target genes, Fos mRNA and protein levels notably decreased after TNF-α treatment or miR-146a overexpression. These changes correlated with a diminution in the DNA-binding activity of AP-1, the Fos-containing transcription factor complex. Interestingly, AP-1 inhibition was accompanied by a reduction in matrix metalloproteinase (MMP)-9 mRNA levels in human cardiac cells. The specific regulation of this MMP by miR-146a was further confirmed at the secretion and enzymatic activity levels, as well as after anti-miR-mediated miR-146a inhibition. The results reported here demonstrate that Fos is a direct target of miR-146a activity and that downregulation of the Fos-AP-1 pathway by miR-146a has the capacity to inhibit MMP-9 activity. Given that MMP-9 is an AP-1 target gene involved in cardiac remodeling, myocardial dysfunction and progression of heart failure, these findings suggest that miR-146a might be a new and promising therapeutic tool for treating cardiac disorders associated with enhanced inflammation in the heart.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Palomer
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Capdevila-Busquets
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
authors.forename: Gaia
authors.initials: G
authors.lastname: Botteri
authors.affiliation: Department of Radiation Oncology, Columbia University, P&S 11-451, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.affiliation: Centro de Investigación Cardiovascular, CSIC-ICCC, IIB-Sant Pau, Avda. Sant Antoni Maria Claret 167, Barcelona 08025, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: Centro de Investigación Cardiovascular, CSIC-ICCC, IIB-Sant Pau, Avda. Sant Antoni Maria Claret 167, Barcelona 08025, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.affiliation: Unitat de Diagnòstic i Teràpia Molecular, Banc de Sang i Teixits, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Vidal
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Barroso
authors.affiliation: Department of Medicine, The Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: Tung O
authors.initials: TO
authors.lastname: Chan
authors.affiliation: Departments of Medicine and Physiology, Cardiovascular Research Center, Temple University School of Medicine, 3500 N, Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain mvazquezcarrera@ub.edu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D007107:Immune System; D007249:Inflammation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Cardiac remodeling; Fos; Inflammation; Matrix metalloproteinase-9; miR-146a