miR-146a targets Fos expression in human cardiac cells
Por:
Palomer, X, Capdevila-Busquets, E, Botteri, G, Davidson, MM, Rodriguez, C, Martinez-Gonzalez, J, Vidal, F, Barroso, E, Chan, TO, Feldman, AM, Vazquez-Carrera, M
Publicada:
1 sep 2015
Resumen:
miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-kappa B, a transcription factor induced by proinflammatory molecules (such as TNF-alpha) 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-alpha. Our results demonstrate that miR-146a transcript levels were sharply increased in cardiac ventricular tissue of transgenic mice with specific overexpression of TNF-alpha in the heart, and also in a cardiomyocyte cell line of human origin (AC16) exposed to TNF-alpha. Among all the in silico predicted miR-146a target genes, Fos mRNA and protein levels notably decreased after TNF-alpha 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, X:
Univ Barcelona, Inst Biomed, Dept Pharmacol & Therapeut Chem, E-08028 Barcelona, Spain
Univ Barcelona, Fac Pharm, CIBER Diabet & Enfermedades Metab Asociadas CIBER, E-08028 Barcelona, Spain
Capdevila-Busquets, E:
Univ Barcelona, Inst Biomed, Dept Pharmacol & Therapeut Chem, E-08028 Barcelona, Spain
Univ Barcelona, Fac Pharm, CIBER Diabet & Enfermedades Metab Asociadas CIBER, E-08028 Barcelona, Spain
Botteri, G:
Univ Barcelona, Inst Biomed, Dept Pharmacol & Therapeut Chem, E-08028 Barcelona, Spain
Univ Barcelona, Fac Pharm, CIBER Diabet & Enfermedades Metab Asociadas CIBER, E-08028 Barcelona, Spain
Davidson, MM:
Columbia Univ, Dept Radiat Oncol, New York, NY 10032 USA
Rodriguez, C:
IIB St Pau, CSIC ICCC, Ctr Invest Cardiovasc, Barcelona 08025, Spain
Martinez-Gonzalez, J:
IIB St Pau, CSIC ICCC, Ctr Invest Cardiovasc, Barcelona 08025, Spain
Vidal, F:
Banc Sang & Teixits, Unitat Diagnost & Terapia Mol, Barcelona 08035, Spain
Barroso, E:
Univ Barcelona, Inst Biomed, Dept Pharmacol & Therapeut Chem, E-08028 Barcelona, Spain
Univ Barcelona, Fac Pharm, CIBER Diabet & Enfermedades Metab Asociadas CIBER, E-08028 Barcelona, Spain
Chan, TO:
Thomas Jefferson Univ, Jefferson Med Coll, Dept Med, Ctr Translat Med, Philadelphia, PA 19107 USA
Feldman, AM:
Temple Univ, Sch Med, Cardiovasc Res Ctr, Dept Med, Philadelphia, PA 19140 USA
Temple Univ, Sch Med, Cardiovasc Res Ctr, Dept Physiol, Philadelphia, PA 19140 USA
Vazquez-Carrera, M:
Univ Barcelona, Inst Biomed, Dept Pharmacol & Therapeut Chem, E-08028 Barcelona, Spain
Univ Barcelona, Fac Pharm, CIBER Diabet & Enfermedades Metab Asociadas CIBER, E-08028 Barcelona, Spain
Gold, Green Published
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