Circ-HIPK3 Strengthens the Effects of Adrenaline in Heart Failure by MiR-17-3p - ADCY6 Axis

Overactivation of β-adrenergic receptor (β-AR) can improve cardiac function temporarily but promotes the development and mortality of heart failure (HF) in the long run. CircRNA, a member of noncoding RNAs, can tolerate digestion of exonuclease and be a chronic stimulator to cell. But the relationship of circRNA with HF remains a puzzle and needs to be explored. Here, we found that circ-HIPK3 affected the concentration of Ca(2+) in cytoplasm by miR-17-3p through ADCY6 (Adenylate cyclase type 6). The increase of ADCY6 caused by circ-HIPK3 was ameliorated by miR-17-3p overexpression and vice versa, implicating the existence of circ-HIPK3 - miR-17-3p - ADCY6 axis. And further assays showed that the level of circ-HIPK3 in heart was upregulated by adrenaline via transcription factor CREB1 (cAMP responsive element-binding protein 1). Experiments in vivo showed downregulation of circ-HIPK3 can alleviate fibrosis and maintain cardiac function post MI in mice. In conclusion, the increased circ-HIPK3 can be a helper for adrenaline but was harmful for heart in the long run and might be an ideal therapeutic target of HF.