MiR-146a targets Fos expression in human cardiac cells
Palomer, Xavier (Universitat de Barcelona)
Capdevila-Busquets, E. (Universitat de Barcelona)
Botteri, G. (Universitat de Barcelona)
Davidson, Mercy M. (Columbia University)
Rodríguez, Cristina (Institut d'Investigació Biomèdica Sant Pau)
Martínez-González, José (Institut d'Investigació Biomèdica Sant Pau)
Vidal, Francisco (Banc de Sang i Teixits)
Barroso, Emma (Universitat de Barcelona)
Chan, Tung O. (Jefferson Medical College)
Feldman, Arthur M. (Temple University School of Medicine)
Vázquez-Carrera, Manuel (Universitat de Barcelona)
Universitat Autònoma de Barcelona

Date:	2015
Abstract:	miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-κB, a transcription factor induced by proinflammatory 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 inhibitionwas 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, aswell 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 bymiR-146a has the capacity to inhibit MMP-9 activity. Given that MMP-9 is an AP-1 target gene involvedin 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.
Grants:	Ministerio de Ciencia e Innovación SAF2009-06939 Ministerio de Economía y Competitividad SAF2012-30708 Ministerio de Economía y Competitividad SAF2012-40127
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Cardiac remodeling ; Fos ; Inflammation ; Matrix metalloproteinase-9 ; Mir-146a
Published in:	Disease Models & Mechanisms, Vol. 8 Núm. 9 (january 2015) , p. 1081-1091, ISSN 1754-8411

DOI: 10.1242/dmm.020768
PMID: 26112171

11 p, 1.2 MB

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