Liraglutide protects high-glucose-stimulated fibroblasts by activating the CD36-JNK-AP1 pathway to downregulate P4HA1

Abstract Background Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus. It’s known that glucagon-like peptide-1 (GLP-1) and prolyl 4-hydroxylase subunit alpha-1 (P4HA1) have significant effect on cardiovascular function, but their interaction in cardiac fibroblasts (CFs) is still being unraveled. Methods and results The present study demonstrated that glucose promotes CFs proliferation and cardiac fibrosis. Using qRT-PCR, Western blot, CCK-8, EdU, flow cytometry, wound healing and Transwell assays to explore the functions of liraglutide and P4HA1 in high-glucose (HG)-induced CFs, we proved that liraglutide as well as silencing of P4HA1 inhibited cell proliferation, migration and invasion, and promoted cell cycle arrest and apoptosis in HG-induced CFs. In addition, liraglutide downregulated P4HA1 expression, upregulated CD36 and P-JNK expression levels, and enhanced the DNA binding activity of AP-1 on P4HA1. Inhibition of CD36 or p--JNK promoted P4HA1 expression. Conclusions Liraglutide may down-regulate P4HA1 expression at least partly though CD36-JNK-AP1 pathway, thereby reducing myocardial fibrosis. Therefore, our study provides novel insight into the molecular mechanism and function of liraglutide in HG-mediated CFs.