The Erk And Akt Signaling Pathways Are Involved In Advanced Glyeation End Product-induced Autophagy In Rat Vascular Smooth Muscle Cells

Advanced glycation end products (AGEs) result from the Maillard reaction, which is a non-enzymatic, irreversible process. Some studies suggest that AGEs accelerate atherosclerosis in type-2diabetic patients with coronary heart disease, In diabetic patients, previous studies have shown that proliferation of vascular smooth muscle cells (VSMCs), a key factor in the development of atherosclerotic lesions, are significantly stimulated by the accumulation of AGEs and their interaction with the receptor for advanced glycation end products (RAGE). Autophagy is an evolutionarily conserved process involving degradation of long-lived proteins. It is important for balancing sources of energy at critical times. In advanced atherosclerotic plaques, autophagy is notably activated by several pathological conditions, such as oxidized lipids, inflammation, oxidative stress and metabolic stress conditions. However, the relationship between AGEs and autophagy in atherosclerotic plaques is rarely reported. AIM:To investigate the effect of advanced glycation end product-induced autophagy in rat vascular smooth muscle cells and to identify the role of autophagy in advanced glycation end product-induced cell proliferation. METHODS:After cultured VSMCs were treated with advanced glycation end products (AGEs) or BSA, protein expression was detected by Western blot and immunofluorescence imaging; autophagosomes were observed by Electron microscopy; cell proliferation was quantified by MTT assay. For function-blocking experiments, we used small interfering RNA molecules (siRNA) targeted to RAGE mRNA. RESULTS:After cultured VSMCs were treated with AGEs, the level of autophagy-associated protein LC3-Ⅱ was up-regulated; the number of autophagosomes was increased. Compared with control group, the cell proliferation of VSMCs was increased in AGE-treated group. Furthermore, pretreating cells with3-MA, an autophagy inhibitor, could decreased this effect. AGEs induced phosphorylation of ERK, JNK, and p38and inhibited phosphorylation of Akt. Furthermore, autophagy in A7R5VSMCs treated with AGEs was reduced when cells were pretreated with the ERK inhibitor PD98059but not by SB203580or SP600125. Activation of the Akt pathway using IGF-1inhibited AGE-induced autophagy. In addition, RNA interference of RAGE decreased AGE-induced autophagy. CONCLUSIONS:AGEs could induce proliferation of VSMCs through mechanisms involving regulation of autophagy through the ERK and Akt signaling pathways. RAGE plays an essential role in AGE-induced autophagy.