Tanshinone IIA inhibits AGEs-induced proliferation and migration of cultured vascular smooth muscle cells by suppressing ERK1/2 MAPK signaling

Document Type : Original Article


Department of Cardiology, the Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China, 310005


Objective(s): Vascular smooth muscle cells (VSMCs) play a key role in the pathogenesis of diabetic vascular disease. Our current study sought to explore the effects of tanshinone IIA on the proliferation and migration of VSMCs induced by advanced glycation end products (AGEs).
Materials and Methods: In this study, we examined the effects of tanshinone IIA by cell proliferation assay and cell migration assay. And we explored the underlying mechanism by Western blotting.
Results: AGEs significantly induced the proliferation and migration of VSMCs, but treatment with tanshinone IIA attenuated these effects. AGEs could increase the activity of the ERK1/2 and p38 pathways but not the JNK pathway. Treatment with tanshinone IIA inhibited the AGEs-induced activation of the ERK1/2 pathway but not the p38 pathway.  
Conclusion: Tanshinone IIA inhibits AGEs-induced proliferation and migration of VSMCs by suppressing the ERK1/2 MAPK signaling pathway.


Main Subjects

1. Allalou A, Nalla A, Prentice KJ, Liu Y, Zhang M, Dai FF, et al. A Predictive metabolic signature for the transition from gestational diabetes to type 2 diabetes. Diabetes 2016; 65:2529-2539.
2. Jain A, Tantia P, Saini K, Sulemani AA, Sirohi P, Rizwani P,              et al. Ratio of waist-to-calf circumference and carotid atherosclerosis in patients of type 2 diabetes mellitus. J Assoc Physicians India 2016; 64:32-35.
3. Berezin AE, Kremzer AA, Berezina TA, Martovitskaya YV. The pattern of circulating microparticles in patients with diabetes mellitus with asymptomatic atherosclerosis. Acta Clin Belgica 2016:38-45.
4. Doran AC, Meller N, Mcnamara CA. Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler Thromb Vasc Biol 2008; 28:812-819.
5. Chen WJ, Lin KH, Lai YJ, Yang SH, Pang JH. Protective effect of propylthiouracil independent of its hypothyroid effect on atherogenesis in cholesterol-fed rabbits: PTEN induction and inhibition of vascular smooth muscle cell proliferation and migration. Circulation 2004; 110:1313-1319.
6. Onalan O, Adar A, Keles H, Ertugrul G, Ozkan N, Aktas H, et al. Onychomycosis is associated with subclinical atherosclerosis in patients with diabetes. Vasa 2015; 44:59-64.
7. He M, Xue ZM, Li J, Zhou BQ. Breviscapine inhibits high glucose-induced proliferation and migration of cultured vascular smooth muscle cells of rats via suppressing the ERK1/2 MAPK signaling pathway. Acta Pharmacol Sin 2012; 33:606-614.
8. Ganguly R, Sahu S, Chavez RJ, Raman P. Trivalent chromium inhibits TSP-1 expression, proliferation, and O-GlcNAc signaling in vascular smooth muscle cells in response to high glucose in vitro. Am J Physiol Cell 2015; 308:C111-22.
9. Liu Y, Wang WM, Zhang XL, He HQ, Sun XL, Zeng H, et al. AGE/RAGE promotes thecalcification of human aortic smooth muscle cells via the Wnt/β-catenin axis. Am J Transl Res 2016; 8:4644-4656.
10. Zeng H, Huang Z, Zhang Y, Sun H. Role of p38MAPK/eNOS signaling pathway in the inhibition of AGEs-induced apoptosis of human umbilical vein endothelial cells by glucagon-like peptide-1. Nan Fang Yi Ke Da Xue Xue Bao 2016; 36:116-119.
11. Forbes JM, Yee LT, Thallas V, Lassila M, Candido R, Jandeleit-Dahm KA, et al. Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis. Diabetes 2004; 53:1813-1823.
12. Basta G, Lazzerini G, Turco SD, 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. Arterioscler Thromb Vasc Biol 2005; 25:1401-1407.
13. Xu B, Chibber R, Ruggiero D, Kohner E, Ritter J, Ferro A, et al. Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products. FASEB J 2003; 17:1289-1291.
14. Li H, Cheng Y, Simoncini T, Xu S. 17β-Estradiol inhibits TNF-α-induced proliferation and migration of vascular smooth muscle cells via suppression of TRAIL. Gynecol Endocrinol 2016; 32:581-586.
15. Quan KT, Park HS, Oh J, Park HB, Ferreira D, Myung CS, et al. Arborinane triterpenoids from rubia philippinensis inhibit proliferation and migration of vascular smooth muscle cells induced by the platelet-derived growth factor. J Nat Prod 2016; 79:2559-2569.
16. Gong Z, Huang C, Sheng X, Zhang Y, Li Q, Wang MW, et al. The role of tanshinone IIA in the treatment of obesity through peroxisome proliferator-activated receptor gamma antagonism. Endocrinology 2009; 150:104-113.
17. Li X, Du JR, Yu Y, Bai B, Zheng XY. Tanshinone IIA inhibits smooth muscle proliferation and intimal hyperplasia in the rat carotid balloon-injured model through inhibition of MAPK signaling pathway. J Ethnopharmacol 2010; 129:273-279.
18. Pan C, Lou L, Huo Y, Singh G, Chen M, Zhang D, et al. Salvianolic acid B and tanshinone IIA attenuate myocardial ischemia injury in mice by NO production through multiple pathways. Ther Adv Cardiovasc Dis 2011; 5:99-111.
19. Wu WY, Yan H, Wang XB, Gui YZ, Gao F, Tang X, et al. Sodium Tanshinone IIA silate inhibits high glucose-induced vascular smooth muscle cell proliferation and migration through activation of amp-activated protein kinase. PloS One 2014; 9:e94957.
20. 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.
21. Lv L, Zhang J, Wang P, Meng Q, Liang W, Zhang L. Zinc finger protein 191 deficiency attenuates vascular smooth muscle cell proliferation, migration, and intimal hyperplasia after endovascular arterial injury. J Vascular Surg 2013; 59(2):500-509.
22. 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.
23. Rubinat E, Marsal JR, Vidal T, Cebrian C, Falguera M, Vilanova MB, et al. Subclinical carotid atherosclerosis in asymptomatic subjects with type 2 diabetes mellitus. J Cardiovasc Nurs 2015; 31:E1-E7.
24. Xiao J, Jin K, Wang J, Jing M, Jin Z, Nan J, et al. Conditional knockout of TFPI-1 in VSMCs of mice accelerates atherosclerosis by enhancing AMOT/YAP pathway. Int J Cardiol 2016; 228:605-614.
25. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 2006; 114:597-605.
26. Jang JY, Kim J, Cai J, Kim Y, Shin K, Kim TS, et al. An ethanolic extract of Angelica gigas improves atherosclerosis by inhibiting vascular smooth muscle cell proliferation. Lab Anim Res 2014; 30:84-89.
27. Yoon YW, Kang TS, Lee BK, Chang W, Hwang KC, Rhee JH, et al. Pathobiological role of advanced glycation endproducts via mitogen-activated protein kinase dependent pathway in the diabetic vasculopathy. Exp Mol Med 2008; 40:398-406.
28. Liang Y, Hou C, Kong J, Wen H, Zheng X, Wu L, et al. HMGB1 binding to receptor for advanced glycation end products enhances inflammatory responses of human bronchial epithelial cells by activating p38 MAPK and ERK1/2. Mol Cell Biochem 2015; 405:63-71.
29. Rzepka R, Dołęgowska B, Sałata D, Rajewska A, Budkowska M, Domański L, et al. Soluble receptors for advanced glycation end products and receptor activator of NF-κB ligand serum levels as markers of premature labor. BMC Pregnancy Childbirth 2015; 15:134.
30. Temaru R, Urakaze M, Satou A, Yamazaki K, Nakamura N, Kobayashi M. High glucose enhances the gene expression of interleukin-8 in human endothelial cells, but not in smooth muscle cells: possible role of interleukin-8 in diabetic macroangiopathy. Diabetologia 1997; 40:610-613.
31. Zhou L, Zuo Z, Chow MS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol 2005; 45:1345–1359.
32. Kim SK, Jung KH, Lee BC. Protective effect of tanshinone IIA on the early stage of experimental diabetic nephropathy. Biol Pharm Bull 2009; 32:220-224.
33. Hwang SL, Yang JH, Jeong YT, Kim YD, Li X, Lu Y, et al. Tanshinone IIA improves endoplasmic reticulum stress-induced insulin resistance through AMP-activated protein kinase. Biochem Biophys Res Commun 2013; 430:1246-1252.