The Functional Role of Zinc Finger E Box-Binding Homeobox 2 (Zeb2) in Promoting Cardiac Fibroblast Activation

Abstract

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.

Dysregulation of the Pdx1/Ovol2/Zeb2 axis in dedifferentiated β-cells triggers the induction of genes associated with epithelial–mesenchymal transition in diabetes

“…Loss of Pdx1 decreases Ovol2 levels and consequently triggers mesenchymal reprogramming of β-cells through the de-repression of EMT-TF Zeb2 . These observations agree with reports indicating that loss of Ovol2 expression is sufficient to trigger EMT reprogramming [ [63] , [64] , [65] ] and that Zeb2 causes mesenchymal reprogramming of different types of cells and contributes to organ fibrosis [ 66 , 67 ]. Furthermore, other β-TFs such as NKX6-1 and NEUROD1 are also recruited to the Ovol2 loci in mouse islets [ 56 ].…”

PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin‐II by reducing TGF‐β1/Smads pathway activation

“…Next, cultured atrial fibroblasts isolated from Ang‐II‐induced mice were subjected to Western blotting, immunofluorescence staining and CCK‐8 assays to assess cell proliferation and differentiation. Especially, α‐SMA, SMemb and ED‐A Fn are main markers of myofibroblast 35 ; in addition, DDR2 determines a‐SMA‐dependent collagen gene expression in the Ang‐II‐induced cardiac fibroblasts. 36 Therefore, we measured the above indicators, and the results further validated the in vivo findings (Figure 3F‐N ).…”

Divergent Effects of Resveratrol on Rat Cardiac Fibroblasts and Cardiomyocytes

“…After 48 h, CF were either treated as outlined below or treated with trypsin and seeded onto new plates at 1:2 ratio and maintained in DMEM-F12 medium with 10% FBS overnight. These cells were considered as myofibroblasts (MF) after 72 h of culture post-isolation (or 24 h after re-seeding) [40,41].…”