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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/149371
miR-146a targets Fos expression in human cardiac cells
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miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-kappaB, a transcription factor induced by pro-inflammatory molecules strongly related to the pathogenesis of cardiac disorders. The main goal of this study consisted in 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, c-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 c-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 matrix metalloproteinase 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 c-Fos is a direct target of miR-146a activity and that c-Fos/AP-1 pathway downregulation 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 may be a new and promising therapeutic tool for treating cardiac disorders associated with enhanced inflammation in the heart.
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PALOMER TARRIDAS, Francesc xavier, CAPDEVILA BUSQUETS, Eva, BOTTERI, Gaia, DAVIDSON, Mercy m., RODRÍGUEZ, Cristina, MARTÍNEZ GONZÁLEZ, José, VIDAL, Francisco, BARROSO FERNÁNDEZ, Emma, CHAN, Tung o., FELDMAN, Arthur m., VÁZQUEZ CARRERA, Manuel. miR-146a targets Fos expression in human cardiac cells. _Disease Models & Mechanisms_. 2015. Vol. 8, núm. 9, pàgs. 1081-1091. [consulta: 5 de desembre de 2025]. ISSN: 1754-8403. [Disponible a: https://hdl.handle.net/2445/149371]