Zeb2: A novel regulator of cardiac fibroblast to myofibroblast transition

Cardiac fibroblast to myofibroblast phenoconversion is a critical step in cardiovascular disease progression. Myofibroblasts contribute to cardiac fibrosis by chronic extracellular matrix remodelling and scar formation which subsequently results in myocardial stiffening, impaired contraction, cardiac dysfunction and eventually to heart failure. Previously we showed that Meox2, a homeobox transcription factor, is highly expressed in fibroblasts compared to myofibroblasts. As well we demonstrated that Meox2 can inhibit myofibroblast phenoconversion by down‐regulating a set of myofibroblast markers. Here we report for the first time that Zeb2, a repressor of Meox2 and an epithelial‐mesenchymal transition inducer, may play a crucial role during this phenoconversion process. Using rat cardiac fibroblasts, we have shown that Zeb2 overexpression causes an up‐regulation of a set of myofibroblast markers‐ SMemb, ED‐A fibronection and α‐SMA. We showed that Zeb2 is highly expressed in myofibroblast nuclei whereas it is only minimally expressed in fibroblasts as observed by immunoblotting and confocal microscopy. Moreover, ectopic Zeb2 expression results in a less migratory phenotype‐ characteristic of mature myofibroblasts. We also showed that Zeb2 overexpression represses Meox2 expression in endothelial cells. We will investigate the role of Zeb2 in myofibroblast proliferation, apoptosis and function in vitro . Thus findings from our study will provide insight to understand the mechanism behind myofibroblast phenoconversion and may provide a basis for developing a Zeb2‐based novel anti‐fibrotic drug in the future.