The role of Akt/mTOR signal in TGF-β-induced arterial endothelial-mesenchymal transition_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

BI Huaqiang ¹ , LIU Hui ¹ , ZHANG Xi ¹ , MA Kuansheng ¹ ,  ZHANG Hui ²

1. Department of Hepatobiliary Surgery, Southwest Hospital, The Third Military University, Chongqing 400038, P.R.China;
2. Department of Radiology Interventional Ward, Southwest Hospital, The Third Military University, Chongqing 400038, P.R.China;

Corresponding author：

ZHANG Hui, Email: 13637912611@163.com

Keywords：

transform growth factor-β; arterial endothelial cell; smooth muscle cell; signal pathway

DOI：

10.7507/1007-9424.201612024

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the molecular signal mechanism of transform growth factor (TGF)-β induced arterial endothelial-mesenchymal transition. Methods Rat arterial endothelial cells were primarily cultured by ex-transplant method. The endothelial cells were incubated by combinant TGF-β (10 ng/mL) for 48 hours and then were detected by immunofluorescence staining and western blotting to observe the cell surface marker expression profile and Akt/mTOR signal activation. On the other hand, the endothelial cells were preincubated by Ly294002 (20 μmol/L) and rapamycin (10 nmol/L) to inhibit the Akt/mTOR signal, and then the cells were further treated with TGF-β (10 ng/mL) for 48 hours to observe the cell surface marker expression profile without Akt/mTOR signal activation. Results Rat artery endothelial cells by TGF-β after incubation, the expressions of smooth muscle cell markers α-smooth muscle actin (α-SMA) and smooth muscle-22α (SM-22α) were up-regulated, and the endothelial cell markers CD31 and vW factor were significantly down-regulated, at the same time, the expressions of phosphorylated Akt and mTOR were also up-regulated. However, after preincubation of Ly294002 (20 μmol/L) and rapamycin (10 nmol/L) to inhibit the phosphorylation of Akt and mTOR signal, above TGF-β-induced expressions of α-SMA and SM-22α in arterial endothelial cells were significantly suppressed and the expressions of CD31 and vWF were preserved. Conclusion TGF-β-induced arterial endothelial-mesenchymal transition is dependent on activation of Akt/mTOR signal, suggesting that Akt/mTOR-dependent arterial endothelial-mesenchymal transition would be one of the mechanisms for intima hyperplasia in transplant arteriosclerosis.

Citation： BI Huaqiang, LIU Hui, ZHANG Xi, MA Kuansheng, ZHANG Hui. The role of Akt/mTOR signal in TGF-β-induced arterial endothelial-mesenchymal transition. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(7): 808-812. doi: 10.7507/1007-9424.201612024 Copy

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3.	Tantravahi J, Womer KL, Kaplan B. Why hasn’t eliminating acute rejection improved graft survival? Annu Rev Med, 2007, 58: 369-385.
4.	Hillebrands JL, Rozing J. Chronic transplant dysfunction and transplant arteriosclerosis: new insights into underlying mechanisms. Expert Rev Mol Med, 2003, 5(2): 1-23.
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7.	Häyry P. Chronic rejection: an update on the mechanism. Transplant Proc, 1998, 30(8): 3993-3995.
8.	Li J, Xiong J, Yang B, et al. Endothelial cell apoptosis induces TGF-β signaling-dependent host endothelial-mesenchymal transition to promote transplant arteriosclerosis. Am J Transplant, 2015, 15(12): 3095-3111.
9.	Cooley BC, Nevado J, Mellad J, et al. TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci Transl Med, 2014, 6(227): 227ra34.
10.	McGuire PG, Orkin RW. Isolation of rat aortic endothelial cells by primary explant techniques and their phenotypic modulation by defined substrata. Lab Invest, 1987, 57(1): 94-105.
11.	Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature, 1993, 362(6423): 801-809.
12.	Katoh Y, Periasamy M. Growth and differentiation of smooth muscle cells during vascular development. Trends Cardiovasc Med, 1996, 6(3): 100-106.
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14.	Grudzinska MK, Kurzejamska E, Bojakowski K, et al. Monocyte chemoattractant protein 1-mediated migration of mesenchymal stem cells is a source of intimal hyperplasia. Arterioscler Thromb Vasc Biol, 2013, 33(6): 1271-1279.
15.	Li J, Liu S, Li W, et al. Vascular smooth muscle cell apoptosis promotes transplant arteriosclerosis through inducing the production of SDF-1alpha. Am J Transplant, 2012, 12(8): 2029-2043.
16.	Rouchaud A, Journé C, Louedec L, et al. Autologous mesenchymal stem cell endografting in experimental cerebrovascular aneurysms. Neuroradiology, 2013, 55(6): 741-749.
17.	Zavadil J, Böttinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene, 2005, 24(37): 5764-5774.
18.	Chu S, Zhang X, Sun Y, et al. Atrial natriuretic peptide: A novel mediator for TGF-β1-induced epithelial-mesenchymal transition in 16HBE-14o and A549 cells. Peptides, 2017, 90: 1-9.
19.	Wang H, Nie L, Wu L, et al. NR2F2 inhibits Smad7 expression and promotes TGF-β-dependent epithelial-mesenchymal transition of CRC via transactivation of miR-21. Biochem Biophys Res Commun, 2017, 485(1): 181-188.
20.	Griggs LA, Hassan NT, Malik RS, et al. Fibronectin fibrils regulate TGF-β1-induced epithelial-mesenchymal transition. Matrix Biol, 2017, 60-61: 157-175.
21.	Jiang Q, Han Y, Gao H, et al. Ursolic acid induced anti-proliferation effects in rat primary vascular smooth muscle cells is associated with inhibition of microRNA-21 and subsequent PTEN/PI3K. Eur J Pharmacol, 2016, 781: 69-75.
22.	Baroja-Mazo A, Revilla-Nuin B, Ramírez P, et al. Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation. World J Transplant, 2016, 6(1): 183-192.
23.	Aggarwal K, Massagué J. Ubiquitin removal in the TGF-β pathway. Nat Cell Biol, 2012, 29, 14(7): 656-657.
24.	Xiao L, Peng X, Liu F, et al. AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by Smurf2 and deubiquitinating enzyme USP4. BMC Cell Biol, 2015, 16: 7.
25.	Cao WH, Liu XP, Meng SL, et al. USP4 promotes invasion of breast cancer cells via Relaxin/TGF-β1/Smad2/MMP-9 signal. Eur Rev Med Pharmacol Sci, 2016, 20(6): 1115-1122.

1. Libby P, Pober JS. Chronic rejection. Immunity, 2001, 14(4): 387-397.
2. Sayegh MH, Carpenter CB. Transplantation 50 years later—progress, challenges, and promises. N Engl J Med, 2004, 351(26): 2761-2766.
3. Tantravahi J, Womer KL, Kaplan B. Why hasn’t eliminating acute rejection improved graft survival? Annu Rev Med, 2007, 58: 369-385.
4. Hillebrands JL, Rozing J. Chronic transplant dysfunction and transplant arteriosclerosis: new insights into underlying mechanisms. Expert Rev Mol Med, 2003, 5(2): 1-23.
5. Rahmani M, Cruz RP, Granville DJ, et al. Allograft vasculopathy versus atherosclerosis. Circ Res, 2006, 99(8): 801-815.
6. Hu Y, Zhang Z, Torsney E, et al. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoEdeficient mice. J Clin Invest, 2004, 113(9): 1258-1265.
7. Häyry P. Chronic rejection: an update on the mechanism. Transplant Proc, 1998, 30(8): 3993-3995.
8. Li J, Xiong J, Yang B, et al. Endothelial cell apoptosis induces TGF-β signaling-dependent host endothelial-mesenchymal transition to promote transplant arteriosclerosis. Am J Transplant, 2015, 15(12): 3095-3111.
9. Cooley BC, Nevado J, Mellad J, et al. TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci Transl Med, 2014, 6(227): 227ra34.
10. McGuire PG, Orkin RW. Isolation of rat aortic endothelial cells by primary explant techniques and their phenotypic modulation by defined substrata. Lab Invest, 1987, 57(1): 94-105.
11. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature, 1993, 362(6423): 801-809.
12. Katoh Y, Periasamy M. Growth and differentiation of smooth muscle cells during vascular development. Trends Cardiovasc Med, 1996, 6(3): 100-106.
13. Yu H, Clarke MC, Figg N, et al. Smooth muscle cell apoptosis promotes vessel remodeling and repair via activation of cell migration, proliferation, and collagen synthesis. Arterioscler Thromb Vasc Biol, 2011, 31(11): 2402-2409.
14. Grudzinska MK, Kurzejamska E, Bojakowski K, et al. Monocyte chemoattractant protein 1-mediated migration of mesenchymal stem cells is a source of intimal hyperplasia. Arterioscler Thromb Vasc Biol, 2013, 33(6): 1271-1279.
15. Li J, Liu S, Li W, et al. Vascular smooth muscle cell apoptosis promotes transplant arteriosclerosis through inducing the production of SDF-1alpha. Am J Transplant, 2012, 12(8): 2029-2043.
16. Rouchaud A, Journé C, Louedec L, et al. Autologous mesenchymal stem cell endografting in experimental cerebrovascular aneurysms. Neuroradiology, 2013, 55(6): 741-749.
17. Zavadil J, Böttinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene, 2005, 24(37): 5764-5774.
18. Chu S, Zhang X, Sun Y, et al. Atrial natriuretic peptide: A novel mediator for TGF-β1-induced epithelial-mesenchymal transition in 16HBE-14o and A549 cells. Peptides, 2017, 90: 1-9.
19. Wang H, Nie L, Wu L, et al. NR2F2 inhibits Smad7 expression and promotes TGF-β-dependent epithelial-mesenchymal transition of CRC via transactivation of miR-21. Biochem Biophys Res Commun, 2017, 485(1): 181-188.
20. Griggs LA, Hassan NT, Malik RS, et al. Fibronectin fibrils regulate TGF-β1-induced epithelial-mesenchymal transition. Matrix Biol, 2017, 60-61: 157-175.
21. Jiang Q, Han Y, Gao H, et al. Ursolic acid induced anti-proliferation effects in rat primary vascular smooth muscle cells is associated with inhibition of microRNA-21 and subsequent PTEN/PI3K. Eur J Pharmacol, 2016, 781: 69-75.
22. Baroja-Mazo A, Revilla-Nuin B, Ramírez P, et al. Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation. World J Transplant, 2016, 6(1): 183-192.
23. Aggarwal K, Massagué J. Ubiquitin removal in the TGF-β pathway. Nat Cell Biol, 2012, 29, 14(7): 656-657.
24. Xiao L, Peng X, Liu F, et al. AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by Smurf2 and deubiquitinating enzyme USP4. BMC Cell Biol, 2015, 16: 7.
25. Cao WH, Liu XP, Meng SL, et al. USP4 promotes invasion of breast cancer cells via Relaxin/TGF-β1/Smad2/MMP-9 signal. Eur Rev Med Pharmacol Sci, 2016, 20(6): 1115-1122.

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The role of Akt/mTOR signal in TGF-β-induced arterial endothelial-mesenchymal transition

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