Abstract Body: Pacing-induced heart failure (HF) in dogs is a well-established model that mimics key features of human dilated cardiomyopathy (DCM) with systolic and diastolic dysfunction. Despite advances in pharmacologic based therapies, DCM exhibits high morbidity and mortality, highlighting the importance of prognostication of disease. Recent studies indicate that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), small nucleolar RNAs (snoRNAs), and circular RNAs (circRNAs), play critical roles in regulators of gene expression, influencing various cellular processes such as transcription, splicing, and translation. However, their roles in cardiac remodeling, fibrosis, and contractile dysfunction, and contribution to the pathogenesis of DCM are still largely unexplored.
Using high-throughput small and long ncRNA sequencing in a canine pacing induced HF model, we profiled the non-coding transcriptome to identify novel regulatory RNAs associated with heart failure. Interestingly, we identified a circular RNA, which we termed circHF, whose expression is elevated in failing canine heart and human DCM and HCM heart tissue. Mechanistically, circHF directly binds and sponge microRNA-29c and increases the expression of ROCK2. Modulating this circRNA–miRNA–mRNA regulatory axis influences cardiomyocyte function in induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Overall, our findings lay an important foundation for understanding the functional role of circHF and its potential relevance to the pathogenesis of human DCM and may facilitate the development of novel therapeutic strategies for human DCM.