MiR-375 Inhibitor Alleviates Inflammation and Oxidative Stress by Upregulating the GPR39 Expression in Atherosclerosis

Atherosclerosis may be caused or developed by an immune response and antioxidation imbalance. MicroRNA-375 (miR-375) or G -protein -coupled receptor 39 (GPR39) is involved in vascular endothelial cell injury, but their role in atherosclerosis is unknown. This experiment aimed to determine the action of the miR375/GPR39 axis in atherosclerosis. Human aortic endothelial cells (HAECs) were treated with 10 ng/mL of oxidised low -density lipoprotein (ox-LDL) for 24 hours to induce HAEC injury, which was treated by the miR-375 inhibitor, GPR39 inhibitor, or agonist. High -fat diet (HFD)-induced ApoE-/- mice were made as an atherosclerosis model for miR-375 inhibitor treatment. Cell Counting Kit -8 was applied to detect HAEC viability. HAEC apoptosis and ROS levels were measured using flow cytometry. Vascular histopathology and the GPR39 expression were detected using hematoxylin-eosin and immunohistochemistry. The expressions of interleukin (IL) -6, IL -1(3, and tumour necrosis factor-alpha (TNF-alpha) were assessed using an enzyme -linked immunosorbent assay. The miR-375, GPR39, NOX-4, and p-IxB alpha/IxB alpha levels were measured using quantitative reverse transcription polymerase chain reaction or western blot. MiR-375 and GPR39 levels increased and decreased in ox-LDL-treated HAECs, respectively. The miR-375 inhibitor or GPR39 agonist promoted cell viability and inhibited apoptosis in ox-LDL-induced HAEC injury. The miR-375 inhibitor also significantly downregulated the IL -6, IL -1(3, TNF-alpha, p-IxB alpha/IxB alpha, ROS, and NOX4 expressions to alleviate oxidative stress and inflammation, which were reversed by the GPR39 inhibitor. An in vivo experiment proved that the miR-375 inhibitor upregulated the GPR39 expression and improved inflammation, oxidative stress, and endothelial cell damage associated with atherosclerosis. The miR-375 inhibitor improved inflammation, oxidative stress, and cell damage in ox-LDL-induced HAECs and HFD-induced ApoE-/- mice by promoting the GPR39 expression, which provided a new theoretical basis for the clinical treatment of atherosclerosis. (Int Heart J 2024; 65: 135-145)