Abstract 12525: TEAD1 is a Novel Regulator of NRF2 and Oxidative Stress Response in Cardiomyocytes

Introduction: TEAD1, the Hippo pathway-regulated transcription factor, has a critical non-redundant role in cardiomyocyte (CM) homeostasis, and its loss-of-function results in acute lethal dilated cardiomyopathy. However, the functional pathways regulated by TEAD1 in CMs remain unclear. Hypothesis: TEAD1 plays an essential role in CM oxidative stress response (OSR) via the regulation of NRF2, the master regulator of antioxidant response. Methods and Results: Conditional CM-specific TEAD1 deletion in adult mice results in acute heart failure (HF) and altered expression of OSR genes. In silico analysis of publicly available RNA-seq data revealed significant downregulation of TEAD1 in dilated and ischemic cardiomyopathy patient hearts and a positive correlation between TEAD1 and NRF2 expression. ChIP-seq with TEAD1 antibody and ATAC-seq revealed that TEAD1 occupied open promoter/enhancer regions of multiple OSR genes, including NRF2 and its targets in adult mouse hearts. Mosaic deletion of TEAD1 in ~50% CMs, which allowed assessment of TEAD1 LOF in CMs without confounding HF effect, reduced NRF2 expression, and increased myocardial oxidative stress indicated by 8OHdG staining (DNA oxidative damage) and cellROX only in TEAD1-deficient CM, but not in CM with normal TEAD1 expression. Ex vivo and in vitro TEAD1 knockout in primary murine adult and neonatal CMs and H9C2 cells resulted in significantly elevated total cellular (Boronate assay) and mitochondrial (mitoSOX) ROS due to reduced NRF2 expression and promoter activity (ARE reporter assay). TEAD1-deficient CM had a lower tolerance to chemically (Angiotensin II, DMNQ, or AntimycinA)-induced oxidative stress. Furthermore, hTEAD1 overexpression was sufficient to significantly increase NRF2-ARE activity and rescue the elevated ROS production in CMs. Conclusions: TEAD1 is a novel cell-autonomous direct transcriptional regulator of NRF2 and CM oxidative stress response.