The role of autophagy in advanced glycation end product-induced proliferation and migration in rat vascular smooth muscle cells

Document Type : Original Article


1 Department of Cardiology, Yidu Central Hospital of Weifang, Qingzhou, Shandong, 262500, China

2 Department of Cardiology, Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, China

3 Department of Cardiology, Zhejiang hospital, Hangzhou, 310013), China


Objective(s): To investigate the role of autophagy in advanced glycation end products (AGEs)-induced proliferation and migration in rat vascular smooth muscle cells (VSMCs).
Materials and Methods: After culture, VSMCs were treated with 0, 1, 10, and 100 μg/ml concentrations of AGEs. Autophagy specific protein light chain 3 (LC3)-I/II was determined by western blotting, autophagosomes were observed with electron microscopy, cell proliferation was quantified using the methyl thiazolyl tetrazolium (MTT) assay, and cell migration was evaluated using Transwell migration and scratch assays.
Results: Compared to the control group, the level of LC3- II/I in AGEs treatment group was up-regulated, and the number of autophagosomes was also increased. Furthermore, in concentration of 100 μg/ml AGEs, the extent of proliferation and migration was significantly increased compared to the control group. However, pretreating cells with autophagy inhibitor 3-MA could attenuate these effects.
Conclusion: Our study demonstrated that AGEs-induced autophagy accelerated AGEs-stimulated proliferation and migration in VSMCs.


Main Subjects

1. Ariosa AR, Klionsky DJ. Long-distance autophagy. Autophagy 2015;11:193-194.
2. Basta G, Lazzerini G, Del Turco S, Ratto GM, Schmidt AM, De Caterina R. At least 2 distinct pathways generating reactive oxygen species mediate vascular cell adhesion molecule-1 induction by advanced glycation end products. Arterioscl Throm Vas 2005;25:1401-1407.
3. Cheong H. Integrating autophagy and metabolism in cancer. Arch Pharm Res    2015;38:358-371.
4. Doran AC, Meller N, McNamara CA. Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscl Throm Vas 2008;28:812-819.
5. Hanssen NM, Beulens JW, van Dieren S, Scheijen JL, van der AD, Spijkerman AM, et al. Plasma advanced glycation end products are associated with incident cardiovascular events in individuals with type 2 diabetes:A case-cohort study with a median follow-up of 10 years (epic-nl). Diabetes 2015;64:257-265.
6. Hou FF, Chertow GM, Kay J, Boyce J, Lazarus JM, Braatz JA, et al. Interaction between beta 2-microglobulin and advanced glycation end products in the development of dialysis related-amyloidosis. Kidney Int 1997;51:1514-1519.
7. Hou X, Hu Z, Xu H, Xu J, Zhang S, Zhong Y , et al. Advanced glycation endproducts trigger autophagy in cadiomyocyte via rage/pi3k/akt/mtor pathway. Cardiovasc Diabetol 2014;13:78.
8. Hu P, Lai D, Lu P, Gao J, He H. Erk and akt signaling pathways are involved in advanced glycation end product-induced autophagy in rat vascular smooth muscle cells. Int J Mol Med 2012;29:613-618.
9. Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 2012;15:545-553.
10. Liu H, Cao Y, Tong T, Shi J, Zhang Y, Yang Y, et al. Autophagy in atherosclerosis: A phenomenon found in human carotid atherosclerotic plaques. Chinese Med J 2015;128:69-74.
11. Martinet W, De Meyer GR. Autophagy in atherosclerosis: A cell survival and death phenomenon with therapeutic potential. Circ Res 2009;104:304-317.
12. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al.  Distinct roles of autophagy in the heart during ischemia and reperfusion: Roles of amp-activated protein kinase and beclin 1 in mediating autophagy. Circ Res 2007;100:914-922.
13. Rebholz CM, Astor BC, Grams ME, Halushka MK, Lazo M, Hoogeveen RC, et al. Association of plasma levels of soluble receptor for advanced glycation end products and risk of kidney disease: The atherosclerosis risk in communities study. Nephrol Dial Transpl 2015;30:77-83.
14. Sakata N, Meng J, Takebayashi S. Effects of advanced glycation end products on the proliferation and fibronectin production of smooth muscle cells. J Atheroscler Thromb 2000;7:169-176.
15. Saraste A, Koskenvuo JW, Airaksinen J, Ramachandran N, Munteanu I, Udd B, et al. No cardiomyopathy in x-linked myopathy with excessive autophagy. Neuromuscular Disord 2015;25:485-487.
16. Wang X, Li L, Li M, Dang X, Wan L, Wang N, et al. Knockdown of mtor by lentivirusmediated rna interference suppresses atherosclerosis and stabilizes plaques via a decrease of macrophages by autophagy in apolipoprotein edeficient mice. Int J Mol Med 2013;32:1215-1221.
17. Yamagishi S, Takeuchi M, Inagaki Y, Nakamura K, Imaizumi T: Role of advanced glycation end products (ages) and their receptor (rage) in the pathogenesis of diabetic microangiopathy. Int J Clin Pharmacol Res 2003;23:129-134.
18. Xie M, Kong Y, Tan W, May H, Battiprolu PK, Pedrozo Z, et al. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation 2014;129:1139-1151.
19. Bodiga VL, Eda SR, Bodiga S: Advanced glycation end products: Role in pathology of diabetic cardiomyopathy. Heart Fail Rev 2014;19:49-63.
20. Yu P, Zhang Y, Li C, Li Y, Jiang S, Zhang X, et al. Class iii pi3k-mediated prolonged activation of autophagy plays a critical role in the transition of cardiac hypertrophy to heart failure. J Cell Mol Med 2015;121:1977-1983.
21. Yoon SJ, Yoon YW, Lee BK, Kwon HM, Hwang KC, Kim M, et al. Potential role of hmg coa reductase inhibitor on oxidative stress induced by advanced glycation endproducts in vascular smooth muscle cells of diabetic vasculopathy. Exp Mol Med 2009;41:802-811.
22. Zhang H, Gong Y, Wang Z, Jiang L, Chen R, Fan X, et al. Apelin inhibits the proliferation and migration of rat pasmcs via the activation of pi3k/akt/mtor signal and the inhibition of autophagy under hypoxia. J Cell Mol Med 2014;18:542-553.