Role of ATOH8 in Mitigating Cardiac Fibrosis in Heart Failure via Inhibition of the Transcriptional Repression of Smad7 by RUNX2.

Cardiac fibrosis is a major driver of heart failure and a key therapeutic target. Here, we demonstrated the role of atonal homologue 8 (ATOH8) in the modulation of cardiac fibrosis in heart failure. The expression of ATOH8 was significantly reduced in patients with heart failure and in the left ventricular tissues of model mice. ATOH8 silencing resulted in the worsening of fibrosis, and adenovirus- induced overexpression of ATOH8 attenuated the progression of cardiac fibrosis under in vitro conditions. RNA sequencing analysis demonstrated that ATOH8 potentially influences cardiac fibrosis by modulating the TGF-/Smad signaling pathway. This was verified through ATOH8 silencing experiments, which showed a marked reduction in the expression of Smad7-a known inhibitor of fibrosis. Further investigation into the molecular mechanisms via immunoprecipitation mass spectrometry indicated that ATOH8 can directly bind to the transcription factor RUNX2, which was found to directly interact with the promoter region of Smad7 to suppress its expression. Accordingly, ATOH8 silencing was found to enhance RUNX2-mediated transcriptional repression of Smad7. The findings collectively imply that ATOH8 attenuates cardiac fibrosis through the RUNX2/Smad7 axis, although interactions with other fibrotic proteins need to be explored further. Through in vivo experiments in model mice of heart failure, we were able to demonstrate that the targeted overexpression of ATOH8 in fibroblasts via adeno-associated virus-9 carrying periostin significantly alleviated cardiac fibrosis and dysfunction induced by transverse aortic constriction surgery. Thus, the findings presented here indicate that ATOH8 potentially represents a novel biomarker and therapeutic target for the attenuation of cardiac fibrosis.