Deletion of delta-like 1 homologue accelerates fibroblast-myofibroblast differentiation and induces myocardial fibrosis
Deletion of delta-like 1 homologue accelerates fibroblast-myofibroblast differentiation and induces myocardial fibrosis
复制标题
DOI：
10.1093/eurheartj/ehy188
复制
发表时间：
2019-03-21
影响因子：
39.3
通讯作者：
Lebeche, Djamel
中科院分区：
文献类型：
--
作者：
Rodriguez, Patricia;Sassi, Yassine;Lebeche, Djamel
目的心肌纤维化与心室结构和几何形状的深刻变化有关，导致心功能下降。目前还没有关于δ样同源物1（Dlk 1）在纤维化反应调节中的作用的信息。在这里，我们调查是否Dlk 1参与心脏成纤维细胞到肌成纤维细胞的分化和调节心肌纤维化，并探讨其影响的分子机制，在这个process.Methods和结果使用Dlk 1基因敲除小鼠和腺病毒基因传递，我们表明，过度表达Dlk 1在心脏成纤维细胞导致成纤维细胞增殖和分化成肌成纤维细胞的抑制。该过程由TGF-1信号传导介导，因为缺乏Dlk 1的分离的成纤维细胞在基线时表现出更高的TGF-1/Smad-3途径活化，导致更早获得肌成纤维细胞表型。同样，Dlk 1-null小鼠显示增加的TGF-1/Smad 3心脏活动，导致肌成纤维细胞的浸润/积聚，结构域外A-纤连蛋白同种型和胶原的诱导和沉积，以及促纤维化标志物的活化。此外，这些促纤维化事件与肌原纤维完整性破坏、肌细胞肥大和心功能障碍相关。有趣的是，Dlk 1的表达在缺血的人和猪心脏组织中下调。在机制上，miR-370通过直接靶向TGF-R2/Smad-3信号传导介导Dlk 1对心脏成纤维细胞-肌成纤维细胞分化的调节，而Dlk 1的经典靶点Notch通路，结论Dlk 1通过干扰TGF/Smad-1表达抑制心肌成纤维细胞向肌成纤维细胞分化。3在心肌中的信号传导。鉴于这种途径的持续激活的有害影响，我们提出Dlk 1作为一种新的潜在候选治疗的情况下，异常的TGF信号转导导致慢性纤维化。
Aims Myocardial fibrosis is associated with profound changes in ventricular architecture and geometry, resulting in diminished cardiac function. There is currently no information on the role of the delta-like homologue 1 (Dlk1) in the regulation of the fibrotic response. Here, we investigated whether Dlk1 is involved in cardiac fibroblast-to-myofibroblast differentiation and regulates myocardial fibrosis and explored the molecular mechanism underpinning its effects in this process.Methods and results Using Dlk1-knockout mice and adenoviral gene delivery, we demonstrate that overexpression of Dlk1 in cardio-fibroblasts resulted in inhibition of fibroblast proliferation and differentiation into myofibroblasts. This process is mediated by TGF-1 signalling, since isolated fibroblasts lacking Dlk1 exhibited a higher activation of the TGF-1/Smad-3 pathway at baseline, leading to an earlier acquisition of a myofibroblast phenotype. Likewise, Dlk1-null mice displayed increased TGF-1/Smad3 cardiac activity, resulting in infiltration/accumulation of myofibroblasts, induction and deposition of extra-domain A-fibronectin isoform and collagen, and activation of pro-fibrotic markers. Furthermore, these profibrotic events were associated with disrupted myofibril integrity, myocyte hypertrophy, and cardiac dysfunction. Interestingly, Dlk1 expression was down-regulated in ischaemic human and porcine heart tissues. Mechanistically, miR-370 mediated Dlk1's regulation of cardiac fibroblast-myofibroblast differentiation by directly targeting TGF-R2/Smad-3 signalling, while the Dlk1 canonical target, Notch pathway, does not seem to play a role in this process.Conclusion These findings are the first to demonstrate an inhibitory role of Dlk1 of cardiac fibroblast-to-myofibroblast differentiation by interfering with TGF/Smad-3 signalling in the myocardium. Given the deleterious effects of continuous activation of this pathway, we propose Dlk1 as a new potential candidate for therapy in cases where aberrant TGF signalling leads to chronic fibrosis.