Circ-AMOTL1 enhances cardiac fibrosis through binding with EIF4A3 and stabilizing MARCKS expression in diabetic cardiomyopathy

OBJECTIVE: To evaluate the effects and possible mechanisms of circular RNAs (circRNAs) on diabetic myocardial fibrosis (DMF). METHODS: We used an in vivo mice model of streptozotocin (STZ)-induced diabetes and conducted in vitro studies using cultured mouse cardiac fibroblast cells (CFs). RESULTS: We found that the expression of circ-AMOTL1 was significantly upregulated in the myocardial tissue of diabetic mice compared to that in normal tissues. Inhibition of circ-AMOTL1 improved cardiac function in mice with type I diabetes and significantly repressed STZ-induced myocardial mesenchymal and perivascular fibrosis. In addition, silencing circ-AMOTL1 inhibited cell proliferation, decreased the expression levels of TGF-β1, collagen 1, collagen III, and α-SMA, and reduced the levels of ROS and NO in HG-treated CFs. Our data also indicated that silencing circ-AMOTL1 significantly reduced the expression of myristoylated alanine-rich C-kinase substrate (MARCKS). Finally, circ-AMOTL1 combined with the RNA-binding protein EIF4A3 to improve MARCKS stability. Moreover, co-transfection with si-circ-AMOTL1 and MARCKS reversed the effects of si-circ-AMOTL1 on cell proliferation, fibrotic marker proteins, and ROS and NO levels in vitro. CONCLUSION: Our data suggest that circ-AMOTL1 plays a key role in STZ-induced DMF by modulating MARCKS, and that targeting circ-AMOTL1 may be a potential strategy to treat DMF.