miR-146a targets Fos expression in human cardiac cells
Por:
Palomer FX, Capdevila-Busquets E, Botteri G, Davidson MM, Rodríguez C, Martínez-González J, Vidal F, Barroso E, Chan TO, Feldman AM and Vazquez M
Publicada:
1 sep 2015
Ahead of Print:
25 jun 2015
Resumen:
miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-?B, a transcription factor induced by pro-inflammatory molecules (such as TNF-a) 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-a. Our results demonstrate that miR-146a transcript levels were sharply increased in cardiac ventricular tissue of transgenic mice with specific overexpression of TNF-a in the heart, and also in a cardiomyocyte cell line of human origin (AC16) exposed to TNF-a. Among all the in silico predicted miR-146a target genes, Fos mRNA and protein levels notably decreased after TNF-a 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.
Filiaciones:
Palomer FX:
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
Capdevila-Busquets E:
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
Botteri G:
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
Davidson MM:
Department of Radiation Oncology, Columbia University, P&S 11-451, 630 West 168th Street, New York, NY 10032, USA
Rodríguez C:
Centro de Investigación Cardiovascular, CSIC-ICCC, IIB-Sant Pau, Avda. Sant Antoni Maria Claret 167, Barcelona 08025, Spain
Martínez-González J:
Centro de Investigación Cardiovascular, CSIC-ICCC, IIB-Sant Pau, Avda. Sant Antoni Maria Claret 167, Barcelona 08025, Spain
Vidal F:
Unitat de Diagnòstic i Teràpia Molecular, Banc de Sang i Teixits, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain
Barroso E:
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
Chan TO:
Department of Medicine, The Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, PA 19107, USA
Feldman AM:
Departments of Medicine and Physiology, Cardiovascular Research Center, Temple University School of Medicine, 3500 N, Broad Street, Philadelphia, PA 19140, USA
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