miR-146a targets Fos expression in human cardiac cells.
miR-146a targets Fos expression in human cardiac cells.
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DOI：
10.1242/dmm.020768
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发表时间：
2015-09
影响因子：
4.3
通讯作者：
Vázquez-Carrera M
中科院分区：
文献类型：
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作者：
Palomer X;Capdevila-Busquets E;Botteri G;Davidson MM;Rodríguez C;Martínez-González J;Vidal F;Barroso E;Chan TO;Feldman AM;Vázquez-Carrera M
miR-146 a是一种微小RNA，其转录水平在NF-κB激活后在心脏中被诱导，NF-κ B是一种由促炎分子（如TNF-α）诱导的转录因子，与心脏疾病的发病机制密切相关。本研究的主要目的包括研究miR-146 a在促炎细胞因子TNF-α引起的心脏病理过程中的新作用。我们的研究结果表明，miR-146 a转录水平急剧增加，在转基因小鼠的心脏中特异性过表达TNF-α的心室组织中，也在暴露于TNF-α的人源性心肌细胞系（AC 16）中。在所有计算机模拟预测的miR-146 a靶基因中，TNF-α处理或miR-146 a过表达后Fos mRNA和蛋白水平显著降低。这些变化与AP-1（含Fos的转录因子复合物）的DNA结合活性降低相关。有趣的是，AP-1抑制伴随着基质金属蛋白酶（MMP）-9在人心肌细胞的mRNA水平的降低。在分泌和酶活性水平以及在抗miR介导的miR-146 a抑制后，进一步证实了miR-146 a对该MMP的特异性调节。本文报道的结果表明，Fos是miR-146 a活性的直接靶标，并且miR-146 a下调Fos-AP-1通路具有抑制MMP-9活性的能力。鉴于MMP-9是AP-1靶基因，参与心脏重塑、心肌功能障碍和心力衰竭的进展，这些发现表明miR-146 a可能是治疗与心脏炎症增强相关的心脏疾病的新的和有前途的治疗工具。总结：这些发现表明，Fos是miR-146 a活性的直接靶点，并且miR-146 a下调Fos-AP-1通路可以抑制MMP-9活性。
miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-κB, a transcription factor induced by pro-inflammatory 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 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. Summary: These findings demonstrate that Fos is a direct target of miR-146a activity and that downregulation of the Fos–AP-1 pathway by miR-146a can inhibit MMP-9 activity.