A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223
K Wang, BO Long, F Liu, JX Wang, CY Liu… - European heart …, 2016 - academic.oup.com
K Wang, BO Long, F Liu, JX Wang, CY Liu, B Zhao, LY Zhou, T Sun, M Wang, T Yu, Y Gong…
European heart journal, 2016•academic.oup.comAims 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 …
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 …
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.
Oxford University Press