Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Ursodeoxycholic Acid (UDCA) Exerts Anti- Atherogenic Effects by Inhibiting Endoplasmic Reticulum (ER) Stress Induced by Disturbed Flow

  • Chung, Jihwa (Medical Research Institute, School of Medicine, Ewha Womans University) ;
  • Kim, Kyoung Hwa (Medical Research Institute, School of Medicine, Ewha Womans University) ;
  • Lee, Seok Cheol (Medical Research Institute, School of Medicine, Ewha Womans University) ;
  • An, Shung Hyun (Medical Research Institute, School of Medicine, Ewha Womans University) ;
  • Kwon, Kihwan (Medical Research Institute, School of Medicine, Ewha Womans University)
  • Received : 2015.04.03
  • Accepted : 2015.07.17
  • Published : 2015.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Disturbed blood flow with low-oscillatory shear stress (OSS) is a predominant atherogenic factor leading to dysfunctional endothelial cells (ECs). Recently, it was found that disturbed flow can directly induce endoplasmic reticulum (ER) stress in ECs, thereby playing a critical role in the development and progression of atherosclerosis. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, has long been used to treat chronic cholestatic liver disease and is known to alleviate endoplasmic reticulum (ER) stress at the cellular level. However, its role in atherosclerosis remains unexplored. In this study, we demonstrated the anti-atherogenic activity of UDCA via inhibition of disturbed flow-induced ER stress in atherosclerosis. UDCA effectively reduced ER stress, resulting in a reduction in expression of X-box binding protein-1 (XBP-1) and CEBP-homologous protein (CHOP) in ECs. UDCA also inhibits the disturbed flow-induced inflammatory responses such as increases in adhesion molecules, monocyte adhesion to ECs, and apoptosis of ECs. In a mouse model of disturbed flow-induced atherosclerosis, UDCA inhibits atheromatous plaque formation through the alleviation of ER stress and a decrease in adhesion molecules. Taken together, our results revealed that UDCA exerts anti-atherogenic activity in disturbed flow-induced atherosclerosis by inhibiting ER stress and the inflammatory response. This study suggests that UDCA may be a therapeutic agent for prevention or treatment of atherosclerosis.

Keywords

References

  1. Beuers, U., Boyer, J.L., and Paumgartner, G. (1998). Ursodeoxycholic acid in cholestasis: Potential mechanisms of action and therapeutic applications. Hepatology 28, 1449-1453. https://doi.org/10.1002/hep.510280601
  2. Bucciarelli, L.G., Wendt, T., Qu, W., Lu, Y., Lalla, E., Rong, L.L., Goova, M.T., Moser, B., Kislinger, T., Lee, D.C., et al. (2002). RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice. Circulation 106, 2827-2835. https://doi.org/10.1161/01.CIR.0000039325.03698.36
  3. Chien, S. (2007). Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am. J. Physiol-Heart C 292, H1209-H1224. https://doi.org/10.1152/ajpheart.01047.2006
  4. Chien, S. (2008). Effects of disturbed flow on endothelial cells. Ann. Biomed. Eng. 36, 554-562. https://doi.org/10.1007/s10439-007-9426-3
  5. Civelek, M., Manduchi, E., Riley, R.J., Stoeckert, C.J., Jr., and Davies, P.F. (2009). Chronic endoplasmic reticulum stress activates unfolded protein response in arterial endothelium in regions of susceptibility to atherosclerosis. Circ. Res. 105, 453-461. https://doi.org/10.1161/CIRCRESAHA.109.203711
  6. Cunningham, K.S., and Gotlieb, A.I. (2005). The role of shear stress in the pathogenesis of atherosclerosis. Lab. Invest. 85, 942-942. https://doi.org/10.1038/labinvest.3700299
  7. Dai, G.H., Kaazempur-Mofrad, M.R., Natarajan, S., Zhang, Y.Z., Vaughn, S., Blackman, B.R., Kamm, R.D., Garcia-Cardena, G., and Gimbrone, M.A. (2004). Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosissusceptible and -resistant regions of human vasculature. Proc. Natl. Acad. Sci. USA 101, 14871-14876. https://doi.org/10.1073/pnas.0406073101
  8. Feaver, R.E., Hastings, N.E., Pryor, A., and Blackman, B.R. (2008). GRP78 upregulation by atheroprone shear stress via p38-, alpha 2 beta 1-dependent mechanism in endothelial cells. Arterioscl. Throm. Vas. 28, 1534-1541. https://doi.org/10.1161/ATVBAHA.108.167999
  9. Gambillara, V., Chambaz, C., Montorzi, G., Roy, S., Stergiopulos, N., and Silacci, P. (2006). Plaque-prone hemodynamics impair endothelial function in pig carotid arteries. Am. J. Physiol. Heart Circ. Physiol. 290, H2320-2328. https://doi.org/10.1152/ajpheart.00486.2005
  10. Gotoh, T., Endo, M., and Oike, Y. (2011). Endoplasmic reticulum stress-related inflammation and cardiovascular diseases. Int. J. Inflamm. 2011, 259462.
  11. Ha, C.H., Wang, W., Jhun, B.S., Wong, C., Hausser, A., Pfizenmaier, K., McKinsey, T.A., Olson, E.N., and Jin, Z.G. (2008). Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis. J. Biol. Chem. 283, 14590-14599. https://doi.org/10.1074/jbc.M800264200
  12. Ha, C.H., Kim, S., Chung, J., An, S.H., and Kwon, K. (2013). Extracorporeal shock wave stimulates expression of the angiogenic genes via mechanosensory complex in endothelial cells: Mimetic effect of fluid shear stress in endothelial cells. Int. J. Cardiol. 168, 4168-4177. https://doi.org/10.1016/j.ijcard.2013.07.112
  13. Heo, K.S., Fujiwara, K., and Abe, J. (2014). Shear stress and atherosclerosis. Mol. Cells 37, 435-440. https://doi.org/10.14348/molcells.2014.0078
  14. Hotamisligil, G.S. (2010). Endoplasmic reticulum stress and atherosclerosis. Nat. Med. 16, 396-399. https://doi.org/10.1038/nm0410-396
  15. Kim, K.M., Pae, H.O., Zheng, M., Park, R., Kim, Y.M., and Chung, H.T. (2007). Carbon monoxide induces heme oxygenase-1 via activation of protein kinase R-like endoplasmic reticulum kinase and inhibits endothelial cell apoptosis triggered by endoplasmic reticulum stress. Circ. Res. 101, 919-927. https://doi.org/10.1161/CIRCRESAHA.107.154781
  16. Kim, S.Y., Kwon, Y.W., Jung, I.L., Sung, J.H., and Park, S.G. (2011). Tauroursodeoxycholate (TUDCA) inhibits neointimal hyperplasia by suppression of ERK via PKCalpha-mediated MKP-1 induction. Cardiovasc. Res. 92, 307-316. https://doi.org/10.1093/cvr/cvr219
  17. Lin, J.H., Li, H., Yasumura, D., Cohen, H.R., Zhang, C., Panning, B., Shokat, K.M., LaVail, M.M., and Walter, P. (2007). IRE1 signaling affects cell fate during the unfolded protein response. Science 318, 944-949. https://doi.org/10.1126/science.1146361
  18. Lindor, K. (2007). Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. New Engl. J. Med. 357, 1524-1529. https://doi.org/10.1056/NEJMct074694
  19. Ma, J., Iida, H., Jo, T., Takano, H., Oonuma, H., Morita, T., Toyo-Oka, T., Omata, M., Nagai, R., Okuda, Y., et al. (2004). Ursodeoxycholic acid inhibits endothelin-1 production in human vascular endothelial cells. Eur. J. Pharmacol. 505, 67-74. https://doi.org/10.1016/j.ejphar.2004.10.042
  20. Marciniak, S.J., Yun, C.Y., Oyadomari, S., Novoa, I., Zhang, Y.H., Jungreis, R., Nagata, K., Harding, H.P., and Ron, D. (2004). CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Gene Dev. 18, 3066-3077. https://doi.org/10.1101/gad.1250704
  21. Nam, D., Ni, C.W., Rezvan, A., Suo, J., Budzyn, K., Llanos, A., Harrison, D., Giddens, D., and Jo, H. (2009). Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis. Am. J. Physiol. Heart Circ. Physiol. 297, H1535-H1543. https://doi.org/10.1152/ajpheart.00510.2009
  22. Passerini, A.G., Polacek, D.C., Shi, C.Z., Francesco, N.M., Manduchi, E., Grant, G.R., Pritchard, W.F., Powell, S., Chang, G.Y., Stoeckert, C.J., et al. (2004). Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta. Proc. Natl. Acad. Sci. USA 101, 2482-2487. https://doi.org/10.1073/pnas.0305938101
  23. Scull, C.M., and Tabas, I. (2011). Mechanisms of ER Stress- Induced Apoptosis in Atherosclerosis. Arterioscl. Throm. Vas. 31, 2792-2797. https://doi.org/10.1161/ATVBAHA.111.224881
  24. Tabas, I. (2009). Macrophage apoptosis in atherosclerosis: consequences on plaque progression and the role of endoplasmic reticulum stress. Antioxid. Redox Signal. 11, 2333-2339. https://doi.org/10.1089/ars.2009.2469
  25. 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
  26. Thorp, E., Li, G., Seimon, T.A., Kuriakose, G., Ron, D., and Tabas, I. (2009). Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe and Ldlr mice lacking CHOP. Cell Metab. 9, 474-481. https://doi.org/10.1016/j.cmet.2009.03.003
  27. Timmins, J.M., Ozcan, L., Seimon, T.A., Li, G., Malagelada, C., Backs, J., Backs, T., Bassel-Duby, R., Olson, E.N., Anderson, M.E., et al. (2009). Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J. Clin. Invest. 119, 2925-2941. https://doi.org/10.1172/JCI38857
  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. Zhang, K.Z., and Kaufman, R.J. (2008). From endoplasmicreticulum stress to the inflammatory response. Nature 454, 455-462. https://doi.org/10.1038/nature07203
  30. Zhou, J., Lhotak, S., Hilditch, B.A., and Austin, R.C. (2005). Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein Edeficient mice. Circulation 111, 1814-1821. https://doi.org/10.1161/01.CIR.0000160864.31351.C1
  31. Zinszner, H., Kuroda, M., Wang, X.Z., 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. Gene Dev. 12, 982-995. https://doi.org/10.1101/gad.12.7.982

Cited by

  1. Ursodeoxycholic acid attenuates experimental autoimmune arthritis by targeting Th17 and inducing pAMPK and transcriptional corepressor SMILE vol.188, 2017, https://doi.org/10.1016/j.imlet.2017.05.011
  2. Neuroprotective Effects of Protein Tyrosine Phosphatase 1B Inhibition against ER Stress-Induced Toxicity vol.40, pp.4, 2017, https://doi.org/10.14348/molcells.2017.2320
  3. Calcium signalling and ER stress in insulin resistance and atherosclerosis vol.280, pp.5, 2016, https://doi.org/10.1111/joim.12562
  4. Bile Acids in the Treatment of Cardiometabolic Diseases vol.16, pp.suppl1, 2015, https://doi.org/10.5604/01.3001.0010.5496
  5. Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome vol.9, pp.None, 2015, https://doi.org/10.3389/fphar.2018.01382
  6. Laminar Flow Inhibits ER Stress-Induced Endothelial Apoptosis through PI3K/Akt-Dependent Signaling Pathway vol.41, pp.11, 2018, https://doi.org/10.14348/molcells.2018.0111
  7. Betulinic acid alleviates endoplasmic reticulum stress‐mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice vol.176, pp.7, 2015, https://doi.org/10.1111/bph.14570
  8. Serum Bile Acid Levels Before and After Sleeve Gastrectomy and Their Correlation with Obesity-Related Comorbidities vol.29, pp.8, 2019, https://doi.org/10.1007/s11695-019-03877-6
  9. Autophagy protects HUVECs against ER stress-mediated apoptosis under simulated microgravity vol.24, pp.9, 2019, https://doi.org/10.1007/s10495-019-01560-w
  10. Coxsackievirus and adenovirus receptor mediates the responses of endothelial cells to fluid shear stress vol.51, pp.11, 2015, https://doi.org/10.1038/s12276-019-0347-7
  11. Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target vol.2020, pp.None, 2015, https://doi.org/10.1155/2020/9270107