Zinc finger BED-type containing 6 (ZBED6) ameliorates cardiac fibrosis by inhibiting Piezo1 transcription and YAP nuclear translocation.

Cardiac fibroblasts progressively replace deceased cardiomyocytes during the development of myocardial fibrosis, an irreversible pathological repair process that ultimately leads to cardiac dysfunction and heart failure. Cardiac injury was evaluated by echocardiography and Masson staining in myocardial  infarction (MI) mice with zinc finger BED-type containing 6 (ZBED6) knockdown or overexpression. Furthermore, chromatin immunoprecipitation (ChIP) assays, electrophoretic mobility shift assays (EMSAs), and luciferase reporter assays were used to explore the target of ZBED6. ZBED6 expression was notably decreased in vivo in MI hearts and in vitro in TGF-β-induced primary mouse cardiac fibroblasts (PMCFs). Transgenic overexpression of ZBED6 specifically in cardiac fibroblasts improved cardiac dysfunction, reduced the infarct area, and decreased the expression levels of fibrotic genes after MI injury. Conversely, physiological knockdown of ZBED6 induced cardiac dysfunction and remodeling, which is consistent with the phenomena observed in vitro. Mechanistically, ZBED6, which functions as a transcriptional inhibitor of Piezo1, failed to prevent its transcription owing to mutations in the promoter binding sites. Stimulation of Piezo1 in PMCFs facilitates YAP translocation into the nucleus, whereas knockdown of Piezo1 or the use of a Piezo1 inhibitor suppresses this translocation. Moreover, the activation of Piezo1 reversed the cardioprotective effects of ZBED6 overexpression. In summary, the protective effect of ZBED6 against myocardial fibrosis injury is achieved through the inhibition of Piezo1 transcription, leading to reduced YAP nuclear translocation. These findings suggest that ZBED6 may become a potential therapeutic target for the clinical treatment of myocardial fibrosis.