Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E0J9, Canada.
Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R2H2A6, Canada.
Int J Mol Sci. 2018 Oct 17;19(10):3207. doi: 10.3390/ijms19103207.
Following cardiac injury, fibroblasts are activated and are termed as myofibroblasts, and these cells are key players in extracellular matrix (ECM) remodeling and fibrosis, itself a primary contributor to heart failure. Nutraceuticals have been shown to blunt cardiac fibrosis in both in-vitro and in-vivo studies. However, nutraceuticals have had conflicting results in clinical trials, and there are no effective therapies currently available to specifically target cardiac fibrosis. We have previously shown that expression of the zinc finger E box-binding homeobox 2 (Zeb2) transcription factor increases as fibroblasts are activated. We now show that Zeb2 plays a critical role in fibroblast activation. Zeb2 overexpression in primary rat cardiac fibroblasts is associated with significantly increased expression of embryonic smooth muscle myosin heavy chain (SMemb), ED-A fibronectin and α-smooth muscle actin (α-SMA). We found that Zeb2 was highly expressed in activated myofibroblast nuclei but not in the nuclei of inactive fibroblasts. Moreover, ectopic Zeb2 expression in myofibroblasts resulted in a significantly less migratory phenotype with elevated contractility, which are characteristics of mature myofibroblasts. Knockdown of Zeb2 with siRNA in primary myofibroblasts did not alter the expression of myofibroblast markers, which may indicate that Zeb2 is functionally redundant with other profibrotic transcription factors. These findings add to our understanding of the contribution of Zeb2 to the mechanisms controlling cardiac fibroblast activation.
心脏损伤后，成纤维细胞被激活并被称为肌成纤维细胞，这些细胞是细胞外基质（ECM）重塑和纤维化的关键参与者，纤维化本身是心力衰竭的主要原因。营养保健品已被证明可在体外和体内研究中减轻心脏纤维化。然而，营养保健品在临床试验中的结果相互矛盾，目前尚无有效的治疗方法可专门针对心脏纤维化。我们之前已经表明，锌指 E 盒结合同源盒 2（Zeb2）转录因子的表达在成纤维细胞被激活时增加。我们现在表明 Zeb2 在成纤维细胞激活中起着关键作用。在原代大鼠心脏成纤维细胞中过表达 Zeb2 与胚胎平滑肌肌球蛋白重链（SMemb）、ED-A 纤维连接蛋白和α-平滑肌肌动蛋白（α-SMA）的表达显著增加有关。我们发现 Zeb2 在活化的肌成纤维细胞核中高度表达，但不在不活跃的成纤维细胞核中表达。此外，在肌成纤维细胞中异位表达 Zeb2 导致迁移表型显著降低，收缩性增加，这是成熟肌成纤维细胞的特征。用 siRNA 敲低原代肌成纤维细胞中的 Zeb2 不会改变肌成纤维细胞标志物的表达，这可能表明 Zeb2 在功能上与其他促纤维化转录因子冗余。这些发现增加了我们对 Zeb2 对控制心脏成纤维细胞激活的机制的贡献的理解。
