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

Abstract

ObjectiveTo evaluate the effects and possible mechanisms of circular RNAs (circRNAs) on diabetic myocardial fibrosis (DMF). MethodsWe used an in vivo mice model of streptozotocin (STZ)-induced diabetes and conducted in vitro studies using cultured mouse cardiac fibroblast cells (CFs). ResultsWe 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. ConclusionOur 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.