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

Abstract

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 Ca2+ 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.

Silencing of circHIPK3 Inhibits Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction by Sponging miR-185-3p

“… 30 circHIPK3 is significantly upregulated during post-myocardial infarction (MI) by sponging miR-17-3p and regulates the activity of adenylate cyclase 6 (ADCY6) and also affects the presence of Ca 2+ in the cytoplasm. 31 Also, circHIPK3 induces proliferation, migration, and development of cardiac fibroblast by sponging miR-29b-3p in angiotensin (AngII)-induced cardiac fibrosis. 32 Exosomal circHIPK3 released from hypoxia-pretreated cardiomyocytes become functionally activated in the cardiac microvascular endothelial cells (CMVECs) under oxidative stress conditions and regulate CMVECs via the miR-29a/Insulin-like growth factor 1 (IGF-1) pathway.…”

CircHIPK3: Key Player in Pathophysiology and Potential Diagnostic and Therapeutic Tool

“…Bai et al found that circHIPK3 promotes myocardial ischemia/reperfusion injury by sponge miR-124-3p ( 24 ). In experiments using mice with myocardial infarction, Deng et al found that circHIPK3 downregulation can reduce cardiac fibrosis and maintain cardiac function ( 25 ). Whether studying cardiac fibrosis or other cardiovascular diseases, scholars have found that circHIPK3 binds miRNA through the sponge mechanism to change the expression of the corresponding protein, thereby affecting the progression of the disease.…”

Effect of Circhipk3 on Polarization of Microglial Cells in Nerve Injury Caused by Heat Radiation

“…CircRNAs have been actively studied because of their increased conservation and increased stability, when compared with linear RNAs [20]. It has been reported that circHIPK3 has cardioprotective and neovascularization effects [21], which can promote the formation of diabetic retina blood vessels [22], and that overexpression of circHIPK3 can inhibit the migration of bladder cancer cells [23]. In our study, we found that the expression of microglial circhipk3 in the HS 0.8 and HS 8 groups gradually increased, as well as in the HS24 group.…”