The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Heat shock protein 90 inhibitor AUY922 attenuates platelet-derived growth factor-BB-induced migration and proliferation of vascular smooth muscle cells

  • Kim, Jisu (Department of Sports Medicine and Science in Graduate School, Konkuk University) ;
  • Lee, Kang Pa (Research & Development Center, UMUST R&D Corporation) ;
  • Kim, Bom Sahn (Department of Nuclear Medicine, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine) ;
  • Lee, Sang Ju (Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Moon, Byung Seok (Department of Nuclear Medicine, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine) ;
  • Baek, Suji (Research & Development Center, UMUST R&D Corporation)
  • Received : 2019.12.05
  • Accepted : 2020.03.25
  • Published : 2020.05.01
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Abstract

Luminespib (AUY922), a heat shock proteins 90 inhibitor, has anti-neoplastic and antitumor effects. However, it is not clear whether AUY922 affects events in vascular diseases. We investigated the effects of AUY922 on the platelet-derived growth factor (PDGF)-BB-stimulated proliferation and migration of vascular smooth muscle cells (VSMC). VSMC viability was detected using the XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reagent. To detect the attenuating effects of AUY922 on PDGF-BB-induced VSMCs migration in vitro, we performed the Boyden chamber and scratch wound healing assays. To identify AUY922-mediated changes in the signaling pathway, the phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) 1/2 was analyzed by immunoblotting. The inhibitory effects of AUY922 on migration and proliferation ex vivo were tested using an aortic ring assay. AUY922 was not cytotoxic at concentrations up to 5 nM. PDGF-BB-induced VSMC proliferation, migration, and sprout outgrowth were significantly decreased by AUY922 in a dose-dependent manner. AUY922 significantly reduced the PDGF-BB-stimulated phosphorylation of Akt and ERK1/2. Furthermore, PD98059 (a selective ERK1/2 inhibitor) and LY294002 (a selective Akt inhibitor) decreased VSMC migration and proliferation by inhibiting phosphorylation of Akt and ERK1/2. Greater attenuation of PDGF-BB-induced cell viability and migration was observed upon treatment with PD98059 or LY294002 in combination with AUY922. AUY922 showed anti-proliferation and anti-migration effects towards PDGF-BB-induced VSMCs by regulating the phosphorylation of ERK1/2 and Akt. Thus, AUY922 is a candidate for the treatment of atherosclerosis and restenosis.

Keywords

References

  1. Frostegard J. Immunity, atherosclerosis and cardiovascular disease. BMC Med . 2013;11:117. https://doi.org/10.1186/1741-7015-11-117
  2. Tousoulis D, Charakida M, Stefanadis C. Endothelial function and inflammation in coronary artery disease. Postgrad Med J . 2008;84:368-371. https://doi.org/10.1136/hrt.2005.066936
  3. Chaabane C, Otsuka F, Virmani R, Bochaton-Piallat ML. Biological responses in stented arteries. Cardiovasc Res. 2013;99:353-363. https://doi.org/10.1093/cvr/cvt115
  4. Won KJ, Jung SH, Lee CK, Na HR, Lee KP, Lee DY, Park ES, Choi WS, Shim SB, Kim B. DJ-1/park7 protects against neointimal formation via the inhibition of vascular smooth muscle cell growth. Cardiovasc Res. 2013;97:553-561. https://doi.org/10.1093/cvr/cvs363
  5. Casscells W. Smooth muscle cell growth factors. Prog Growth Factor Res. 1991;3:177-206. https://doi.org/10.1016/0955-2235(91)90006-P
  6. Jawien A, Bowen-Pope DF, Lindner V, Schwartz SM, Clowes AW. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest. 1992;89:507-511. https://doi.org/10.1172/JCI115613
  7. Campbell M, Trimble ER. Modification of PI3K- and MAPK-dependent chemotaxis in aortic vascular smooth muscle cells by protein kinase CbetaII. Circ Res . 2005;96:197-206. https://doi.org/10.1161/01.RES.0000152966.88353.9d
  8. Moser C, Lang SA, Stoeltzing O. Heat-shock protein 90 (Hsp90) as a molecular target for therapy of gastrointestinal cancer. Anticancer Res. 2009;29:2031-2042.
  9. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22:1276-1312. https://doi.org/10.1101/gad.1653708
  10. Zhao Z, Wang Y, Li S, Liu S, Liu Y, Yu Y, Yang F, Xu Z, Wang G. HSP90 inhibitor 17-DMAG effectively alleviated the progress of thoracic aortic dissection by suppressing smooth muscle cell phenotypic switch. Am J Transl Res. 2019;11:509-518.
  11. Kim J, Jang SW, Park E, Oh M, Park S, Ko J. The role of heat shock protein 90 in migration and proliferation of vascular smooth muscle cells in the development of atherosclerosis. J Mol Cell Cardiol. 2014;72:157-167. https://doi.org/10.1016/j.yjmcc.2014.03.008
  12. Okamoto J, Mikami I, Tominaga Y, Kuchenbecker KM, Lin YC, Bravo DT, Clement G, Yagui-Beltran A, Ray MR, Koizumi K, He B, Jablons DM. Inhibition of Hsp90 leads to cell cycle arrest and apoptosis in human malignant pleural mesothelioma. J Thorac Oncol. 2008;3:1089-1095. https://doi.org/10.1097/jto.0b013e3181839693
  13. Chen Y, Wang X, Cao C, Wang X, Liang S, Peng C, Fu L, He G. Inhibition of HSP90 sensitizes a novel Raf/ERK dual inhibitor CY-9d in triple-negative breast cancer cells. Oncotarget. 2017;8:104193-104205. https://doi.org/10.18632/oncotarget.22119
  14. Baek S, Lee KP, Cui L, Ryu Y, Hong JM, Kim J, Jung SH, Bae YM, Won KJ, Kim B. Low-power laser irradiation inhibits PDGF-BBinduced migration and proliferation via apoptotic cell death in vascular smooth muscle cells. Lasers Med Sci. 2017;32:2121-2127. https://doi.org/10.1007/s10103-017-2338-z
  15. Li Y, Zhang T, Schwartz SJ, Sun D. New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Updat. 2009;12:17-27. https://doi.org/10.1016/j.drup.2008.12.002
  16. Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med. 2002;8:1249-1256. https://doi.org/10.1038/nm1102-1249
  17. Kang H, Ahn DH, Pak JH, Seo KH, Baek NI, Jang SW. Magnobovatol inhibits smooth muscle cell migration by suppressing PDGF-$R{\beta}$ phosphorylation and inhibiting matrix metalloproteinase-2 expression. Int J Mol Med. 2016;37:1239-1246. https://doi.org/10.3892/ijmm.2016.2548
  18. Millette E, Rauch BH, Defawe O, Kenagy RD, Daum G, Clowes AW. Platelet-derived growth factor-BB-induced human smooth muscle cell proliferation depends on basic FGF release and FGFR-1 activation. Circ Res. 2005;96:172-179. https://doi.org/10.1161/01.RES.0000154595.87608.db
  19. Raica M, Cimpean AM. Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. Pharmaceuticals (Basel). 2010;3:572-599. https://doi.org/10.3390/ph3030572
  20. Vabulas RM, Raychaudhuri S, Hayer-Hartl M, Hartl FU. Protein folding in the cytoplasm and the heat shock response. Cold Spring Harb Perspect Biol. 2010;2:a004390. https://doi.org/10.1101/cshperspect.a004390
  21. Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer. 2010;10:537-549. https://doi.org/10.1038/nrc2887
  22. Jiao Y, Ou W, Meng F, Zhou H, Wang A. Targeting HSP90 in ovarian cancers with multiple receptor tyrosine kinase coactivation. Mol Cancer. 2011;10:125. https://doi.org/10.1186/1476-4598-10-125
  23. Porsch H, Mehic M, Olofsson B, Heldin P, Heldin CH. Plateletderived growth factor $\beta$-receptor, transforming growth factor $\beta$ type I receptor, and CD44 protein modulate each other's signaling and stability. J Biol Chem. 2014;289:19747-19757. https://doi.org/10.1074/jbc.M114.547273
  24. Won KJ, Park SH, Park T, Lee CK, Lee HM, Choi WS, Kim SJ, Park PJ, Jang HK, Kim SH, Kim B. Cofilin phosphorylation mediates proliferation in response to platelet-derived growth factor-BB in rat aortic smooth muscle cells. J Pharmacol Sci. 2008;108:372-329. https://doi.org/10.1254/jphs.FP0072354
  25. Namkoong S, Kim CK, Cho YL, Kim JH, Lee H, Ha KS, Choe J, Kim PH, Won MH, Kwon YG, Shim EB, Kim YM. Forskolin increases angiogenesis through the coordinated cross-talk of PKAdependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling. Cell Signal. 2009;21:906-915. https://doi.org/10.1016/j.cellsig.2009.01.038
  26. ten Freyhaus H, Huntgeburth M, Wingler K, Schnitker J, Baumer AT, Vantler M, Bekhite MM, Wartenberg M, Sauer H, Rosenkranz S. Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. Cardiovasc Res. 2006; 71:331-341. https://doi.org/10.1016/j.cardiores.2006.01.022
  27. Oliveira JSS, Santos GDS, Moraes JA, Saliba AM, Barja-Fidalgo TC, Mattos-Guaraldi AL, Nagao PE. Reactive oxygen species generation mediated by NADPH oxidase and PI3K/Akt pathways contribute to invasion of Streptococcus agalactiae in human endothelial cells. Mem Inst Oswaldo Cruz . 2018;113:e140421.
  28. Nguyen Thi PA, Chen MH, Li N, Zhuo XJ, Xie L. PD98059 protects brain against cells death resulting from ROS/ERK activation in a cardiac arrest rat model. Oxid Med Cell Longev. 2016;2016:3723762.