Semaglutide attenuates diabetic vascular calcification by enhancing autophagy and lysosomal function via targeting CPNE1.

Patients with diabetes exhibit an increased susceptibility to vascular calcification, which is associated with significantly elevated risks of mortality and disability. As a new Glucagon-like peptide-1 receptor agonist, Semaglutide is primarily indicated for type 2 diabetes mellitus and obesity, while also demonstrating definitive cardiovascular protective effects. However, the effect of semaglutide on diabetic vascular calcification remains unknown. Our results demonstrated a dose-dependent reduction in calcium deposition with Semaglutide treatment, which was accompanied by downregulation of RUNX2 and BMP2 protein expression in aortic tissues. Additionally, Semaglutide also conferred protective effects in AGE-BSA stimulated mouse aortic smooth muscle cells (MOVAS). Autophagy, a lysosomal degradation pathway, is intimately involved in the pathological process of diabetic vascular calcification. During stimulation with AGEs-BSA, impaired lysosomal function and blocked autophagic flux were observed, as evidenced by increased protein levels of LC3-II and P62, alongside decreased expression of CTSD, CTSB, LAMP1 and LAMP2. These changes were accompanied by a decline in lysosomal pH, activity, and degradative capacity. Treatment with Semaglutide mitigated these abnormalities, restoring autophagic flux and lysosomal function, and consequently attenuating AGEs-BSA-induced calcification in MOVAS. Combined bioinformatics and Western blot analysis confirmed the significant downregulation of CPNE1 by Semaglutide in AGEs-BSA stimulated MOVAS. Copine-1 (CPNE1), a member of the copine protein family, is characterized as a calcium-dependent phospholipid-binding protein that primarily resides in the cytoplasm. These findings indicate that the attenuation of diabetic vascular calcification (DVC) by Semaglutide is associated with the inhibition of CPNE1-mediated autophagy, suggesting a potential novel therapeutic strategy for managing DVC.