MiR-146a targets Fos expression in human cardiac cells
Palomer, Xavier (Universitat de Barcelona)
Capdevila Busquets, Eva (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 (Universitat Autònoma de Barcelona. 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

Data:	2015
Resum:	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.
Ajuts:	Ministerio de Ciencia e Innovación SAF2009-06939 Ministerio de Economía y Competitividad SAF2012-30708 Ministerio de Economía y Competitividad SAF2012-40127
Drets:	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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cardiac remodeling ; Fos ; Inflammation ; Matrix metalloproteinase-9 ; Mir-146a
Publicat a:	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

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats