A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR 223.
AIMS Sustained cardiac hypertrophy accompanied by maladaptive cardiac remodelling represents an early event in the clinical course leading to heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. However, the molecular mechanisms that regulate cardiac hypertrophy are largely unknown. METHODS AND RESULTS Here we show that a circular RNA (circRNA) which we term heart related circRNA (HRCR) acts as an endogenous miR 223 sponge to inhibit cardiac hypertrophy and heart failure. miR 223 transgenic mice developed cardiac hypertrophy and heart failure, whereas miR 223 deficient mice were protected from hypertrophic stimuli, indicating that miR 223 acts as a positive regulator of cardiac hypertrophy. We identified ARC as a miR 223 downstream target to mediate the function of miR 223 in cardiac hypertrophy. Apoptosis repressor with CARD domain transgenic mice showed reduced hypertrophic responses. Further, we found that a circRNA HRCR functions as an endogenous miR 223 sponge to sequester and inhibit miR 223 activity, which resulted in the increase of ARC expression. Heart related circRNA directly bound to miR 223 in cytoplasm and enforced expression of HRCR in cardiomyocytes and in mice both exhibited attenuated hypertrophic responses. CONCLUSIONS These findings disclose a novel regulatory pathway that is composed of HRCR, miR 223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.
European heart journal