| First Author | Palomer X | Year | 2015 |
| Journal | Dis Model Mech | Volume | 8 |
| Issue | 9 | Pages | 1081-91 |
| PubMed ID | 26112171 | Mgi Jnum | J:225727 |
| Mgi Id | MGI:5694281 | Doi | 10.1242/dmm.020768 |
| Citation | Palomer X, et al. (2015) miR-146a targets Fos expression in human cardiac cells. Dis Model Mech 8(9):1081-91 |
| abstractText | 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 (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. |
