Background: The glucagon-like peptide-1 (GLP-1) receptor agonistliraglutide (LIRA) is a potential hypoglycemic drug with antiatherosclerosis(AS) effects. Autophagy in the vascular smooth musclecells (VSMCs) facilitates AS. However, the role of autophagy in theanti-AS mechanism of LIRA remains unclear.
Aims: To examine the role and mechanisms of autophagy in LIRA’simprovement of the biological characteristics of VSMCs in highglucose conditions.
Study Design: A VSMC injury model induced by high glucoseconcentrations was used to detect the regulatory effects of LIRAon VSMC autophagy, calcification, migration, proliferation andphenotype conversion.
Methods: VSMCs isolated from the thoracic aorta of male SDrats were subjected to a high glucose (HG) condition (25 mM) inDulbecco’s Modified Eagle’s Medium with or without LIRA, the GLP-1 receptor antagonist exendin9-39 (Exe9-39), a phosphatidylinositol3-kinase (PI3K) inhibitor (LY294002), and autophagy inhibitors(3-methyladenine [3-MA] and bafilomycin A1 [Baf A1]). Acridineorange staining, western blotting, transmission electron microscopy,and mCherry-GFP-LC3 transfection were performed to evaluatethe autophagy flux. Additionally, VSMC migration, calcification,proliferation, and apoptosis in HG conditions were observed.Results: Addition of LIRA alone or in combination with autophagyinhibitors significantly downregulated Beclin, increased the LC3-II/LC3-I ratio, and upregulated p62 in VSMCs in HG conditions.Furthermore, autophagolysosome formation was markedly curbedafter treatment with LIRA and/or autophagy inhibitors. Inhibition ofautophagy by LIRA and/or the autophagy inhibitors attenuated VSMCphenotype conversion, proliferation, migration, and calcification andpromoted VSMC apoptosis in HG conditions. This protective role ofLIRA was augmented by LY294002, but inhibited by Exe9-39.Conclusion: LIRA plays a significant role in the improvement of thebiological features of VSMCs in HG conditions.