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Laminar Flow Inhibits ER Stress-Induced Endothelial Apoptosis through PI3K/Akt-Dependent Signaling Pathway

  • Kim, Suji (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine) ;
  • Woo, Chang-Hoon (Department of Pharmacology and Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine)
  • Received : 2018.03.11
  • Accepted : 2018.10.23
  • Published : 2018.11.30

Abstract

Atherosclerosis preferentially involves in prone area of low and disturbed blood flow while steady and high levels of laminar blood flow are relatively protected from atherosclerosis. Disturbed flow induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). ER stress is caused under stress that disturbs the processing and folding of proteins resulting in the accumulation of misfolded proteins in the ER and activation of the UPR. Prolonged or severe UPR leads to activate apoptotic signaling. Recent studies have indicated that disturbed flow significantly up-regulated $p-ATF6{\alpha}$, $p-IRE1{\alpha}$, and its target spliced XBP-1. However, the role of laminar flow in ER stress-mediated endothelial apoptosis has not been reported yet. The present study thus investigated the role of laminar flow in ER stress-dependent endothelial cell death. The results demonstrated that laminar flow protects ER stress-induced cleavage forms of PARP-1 and caspase-3. Also, laminar flow inhibits ER stress-induced $p-eIF2{\alpha}$, ATF4, CHOP, spliced XBP-1, ATF6 and JNK pathway; these effects are abrogated by pharmacological inhibition of PI3K with wortmannin. Finally, nitric oxide affects thapsigargin-induced cell death in response to laminar flow but not UPR. Taken together, these findings indicate that laminar flow inhibits UPR and ER stress-induced endothelial cell death via PI3K/Akt pathway.

Keywords

References

  1. Brown, M.K., and Naidoo, N. (2012). The endoplasmic reticulum stress response in aging and age-related diseases. Front. Physiol. 3.
  2. Chen, K.D., Li, Y.S., Kim, M., Li, S., Yuan, S., Chien, S., and Shyy, J.Y. (1999). Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J. Biol. Chem. 274, 18393-18400. https://doi.org/10.1074/jbc.274.26.18393
  3. Chung, J., Kim, K.H., Lee, S.C., An, S.H., and Kwon, K. (2015). Ursodeoxycholic acid (UDCA) exerts anti-atherogenic effects by inhibiting endoplasmic reticulum (ER) stress induced by disturbed flow. Mol. Cells 38, 851-858. https://doi.org/10.14348/molcells.2015.0094
  4. Davies, P.F., Civelek, M., Fang, Y., and Fleming, I. (2013). The atherosusceptible endothelium: endothelial phenotypes in complex haemodynamic shear stress regions in vivo. Cardiovasc. Res. 99, 315-327. https://doi.org/10.1093/cvr/cvt101
  5. Davis, M.E., Grumbach, I.M., Fukai, T., Cutchins, A., and Harrison, D.G. (2004). Shear stress regulates endothelial nitric-oxide synthase promoter activity through nuclear factor kappaB binding. J. Biol. Chem. 279, 163-168. https://doi.org/10.1074/jbc.M307528200
  6. Ettlinger, C., Schindler, J., and Lehle, L. (1986). Cell-cycle arrest of plant suspension cultures by tunicamycin. Planta 168, 101-105. https://doi.org/10.1007/BF00407015
  7. Fleming, I., Bauersachs, J., Fisslthaler, B., and Busse, R. (1998). $Ca^{2+}$-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress. Circ. Res. 82, 686-695. https://doi.org/10.1161/01.RES.82.6.686
  8. Fujii, J., Wood, K., Matsuda, F., Carneiro-Filho, B.A., Schlegel, K.H., Yutsudo, T., Binnington-Boyd, B., Lingwood, C.A., Obata, F., Kim, K.S., et al. (2008). Shiga toxin 2 causes apoptosis in human brain microvascular endothelial cells via C/EBP homologous protein. Infect Immun. 76, 3679-3689. https://doi.org/10.1128/IAI.01581-07
  9. Greene, C.M., and McElvaney, N.G. (2010). Protein misfolding and obstructive lung disease. Proc. Am. Thorac. Soc. 7, 346-355. https://doi.org/10.1513/pats.201002-019AW
  10. Guo, D., Chien, S., and Shyy, J.Y. (2007). Regulation of endothelial cell cycle by laminar versus oscillatory flow: distinct modes of interactions of AMP-activated protein kinase and Akt pathways. Circ. Res. 100, 564-571. https://doi.org/10.1161/01.RES.0000259561.23876.c5
  11. Hahn, C., and Schwartz, M.A. (2009). Mechanotransduction in vascular physiology and atherogenesis. Nat. Rev. Mol. Cell. Biol. 10, 53-62. https://doi.org/10.1038/nrm2596
  12. Kim, M., Kim, S., Lim, J.H., Lee, C., Choi, H.C., and Woo, C.H. (2012). Laminar flow activation of ERK5 protein in vascular endothelium leads to atheroprotective effect via NF-E2-related factor 2 (Nrf2) activation. J. Biol. Chem. 287, 40722-40731. https://doi.org/10.1074/jbc.M112.381509
  13. Kuchan, M.J., Jo, H., and Frangos, J.A. (1994). Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells. Am. J. Physiol. 267, C753-758. https://doi.org/10.1152/ajpcell.1994.267.3.C753
  14. Lenna, S., Han, R., and Trojanowska, M. (2014). Endoplasmic reticulum stress and endothelial dysfunction. IUBMB Life 66, 530-537. https://doi.org/10.1002/iub.1292
  15. Li, Y.S., Haga, J.H., and Chien, S. (2005). Molecular basis of the effects of shear stress on vascular endothelial cells. J. Biomech. 38, 1949-1971. https://doi.org/10.1016/j.jbiomech.2004.09.030
  16. Malek, A.M., Alper, S.L., and Izumo, S. (1999). Hemodynamic shear stress and its role in atherosclerosis. Jama 282, 2035-2042. https://doi.org/10.1001/jama.282.21.2035
  17. Nigro, P., Abe, J., and Berk, B.C. (2011). Flow shear stress and atherosclerosis: a matter of site specificity. Antioxidants & Redox Signaling 15, 1405-1414. https://doi.org/10.1089/ars.2010.3679
  18. Oslowski, C.M., and Urano, F. (2011). Measuring ER stress and the unfolded protein response using mammalian tissue culture system. Method. Enzymol. 490, 71-92.
  19. Schroder, M., and Kaufman, R.J. (2005). ER stress and the unfolded protein response. Mutat. Res. 569, 29-63. https://doi.org/10.1016/j.mrfmmm.2004.06.056
  20. Shiojima, I., and Walsh, K. (2002). Role of Akt signaling in vascular homeostasis and angiogenesis. Circ. Res. 90, 1243-1250. https://doi.org/10.1161/01.RES.0000022200.71892.9F
  21. Szegezdi, E., Logue, S.E., Gorman, A.M., and Samali, A. (2006). Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7, 880-885. https://doi.org/10.1038/sj.embor.7400779
  22. Tabas, I. (2010). The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ. Res. 107, 839-850. https://doi.org/10.1161/CIRCRESAHA.110.224766
  23. Takabe, W., Jen, N., Ai, L., Hamilton, R., Wang, S., Holmes, K., Dharbandi, F., Khalsa, B., Bressler, S., Barr, M.L., et al. (2011). Oscillatory shear stress induces mitochondrial superoxide production: implication of NADPH oxidase and c-Jun NH2-terminal kinase signaling. Antioxid. Redox Sign. 15, 1379-1388. https://doi.org/10.1089/ars.2010.3645
  24. Vai, M., Popolo, L., and Alberghina, L. (1987). Effect of tunicamycin on cell cycle progression in budding yeast. Exp. Cell Res. 171, 448-459. https://doi.org/10.1016/0014-4827(87)90176-5
  25. van Thienen, J.V., Fledderus, J.O., Dekker, R.J., Rohlena, J., van Ijzendoorn, G.A., Kootstra, N.A., Pannekoek, H., and Horrevoets, A.J. (2006). Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization. Cardiovasc. Res. 72, 231-240. https://doi.org/10.1016/j.cardiores.2006.07.008
  26. Xiao, Z., Zhang, Z., Ranjan, V., and Diamond, S.L. (1997). Shear stress induction of the endothelial nitric oxide synthase gene is calcium-dependent but not calcium-activated. J. Cell. Physiol. 171, 205-211. https://doi.org/10.1002/(SICI)1097-4652(199705)171:2<205::AID-JCP11>3.0.CO;2-C
  27. Yan, C., Takahashi, M., Okuda, M., Lee, J.D., and Berk, B.C. (1999). Fluid shear stress stimulates big mitogen-activated protein kinase 1 (BMK1) activity in endothelial cells. Dependence on tyrosine kinases and intracellular calcium. J. Biol. Chem. 274, 143-150. https://doi.org/10.1074/jbc.274.1.143
  28. Zeng, L., Zampetaki, A., Margariti, A., Pepe, A.E., Alam, S., Martin, D., Xiao, Q., Wang, W., Jin, Z.G., Cockerill, G., et al. (2009). Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proc. Natl. Acad. Sci. USA 106, 8326-8331. https://doi.org/10.1073/pnas.0903197106
  29. Zinszner, H., Kuroda, M., Wang, X., Batchvarova, N., Lightfoot, R.T., Remotti, H., Stevens, J.L., and Ron, D. (1998). CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes. Dev. 12, 982-995. https://doi.org/10.1101/gad.12.7.982

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