MG-132 activates sodium palmitate-induced autophagy in human vascular smooth muscle cells and inhibits senescence via the PI3K/AKT/mTOR axis

Abstract

Abstract Objective This study aimed to reveal the role and mechanism of MG-132 in delaying hyperlipidemia-induced senescence of vascular smooth muscle cells (VSMCs). Methods Immunohistochemistry and hematoxylin-eosin staining confirmed the therapeutic effect of MG-132 on arterial senescence in vivo and its possible mechanism. Subsequently, VSMCs were treated with sodium palmitate (PA), an activator (Recilisib) or an inhibitor (Pictilisib) to activate or inhibit PI3K, and CCK-8 and EdU staining, wound healing assays, Transwell cell migration assays, autophagy staining assays, reactive oxygen species assays, senescence-associated β-galactosidase staining, and Western blotting were performed to determine the molecular mechanism by which MG-132 inhibits VSMC senescence. Validation of the interaction between MG-132 and PI3K using molecular docking. Results Increased expression of p-PI3K, a key protein of the autophagy regulatory system, and decreased expression of the autophagy-associated proteins Beclin 1 and ULK1 were observed in the aortas of C57BL/6J mice fed a high-fat diet (HFD), and autophagy was inhibited in aortic smooth muscle. MG-132 inhibits atherosclerosis by activating autophagy in VSMCs to counteract PA-induced cell proliferation, migration, oxidative stress, and senescence, thereby inhibiting VSMC senescence in the aorta. This process is achieved through the PI3K/AKT/mTOR signaling pathway. Conclusion MG-132 activates autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby inhibiting palmitate-induced proliferation, migration, and oxidative stress in vascular smooth muscle cells and suppressing their senescence.

Keywords

• MG-132
• Sodium palmitate
• Hyperlipidemia
• PI3K
• Autophagy
• Senescence