Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Recombinant Human Thioredoxin-1 Protects Macrophages from Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation and Cell Apoptosis

  • Zhang, Hui (Department of Cardiology, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, the Second Affiliated Hospital of Harbin Medical University) ;
  • Liu, Qi (Department of Cardiology, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, the Second Affiliated Hospital of Harbin Medical University) ;
  • Lin, Jia-Le (Department of Cardiology, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, the Second Affiliated Hospital of Harbin Medical University) ;
  • Wang, Yu (Department of Cardiology, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, the Second Affiliated Hospital of Harbin Medical University) ;
  • Zhang, Ruo-Xi (Department of Cardiology, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, the Second Affiliated Hospital of Harbin Medical University) ;
  • Hou, Jing-Bo (Department of Cardiology, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, the Second Affiliated Hospital of Harbin Medical University) ;
  • Yu, Bo (Department of Cardiology, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, the Second Affiliated Hospital of Harbin Medical University)
  • Received : 2016.12.13
  • Accepted : 2017.02.07
  • Published : 2018.03.01
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Abstract

Oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and apoptosis play critical roles in the pathogenesis of atherosclerosis. Thioredoxin-1 (Trx) is an antioxidant that potently protects various cells from oxidative stress-induced cell death. However, the protective effect of Trx on ox-LDL-induced macrophage foam cell formation and apoptosis has not been studied. This study aims to investigate the effect of recombinant human Trx (rhTrx) on ox-LDL-stimulated RAW264.7 macrophages and elucidate the possible mechanisms. RhTrx significantly inhibited ox-LDL-induced cholesterol accumulation and apoptosis in RAW264.7 macrophages. RhTrx also suppressed the ox-LDL-induced overproduction of lectin-like oxidized LDL receptor (LOX-1), Bax and activated caspase-3, but it increased the expression of Bcl-2. In addition, rhTrx markedly inhibited the ox-LDL-induced production of intracellular reactive oxygen species (ROS) and phosphorylation of p38 mitogen-activated protein kinases (MAPK). Furthermore, anisomycin (a p38 MAPK activator) abolished the protective effect of rhTrx on ox-LDL-stimulated RAW264.7 cells, and SB203580 (a p38 MAPK inhibitor) exerted a similar effect as rhTrx. Collectively, these findings indicate that rhTrx suppresses ox-LDL-stimulated foam cell formation and macrophage apoptosis by inhibiting ROS generation, p38 MAPK activation and LOX-1 expression. Therefore, we propose that rhTrx has therapeutic potential in the prevention and treatment of atherosclerosis.

Keywords

References

  1. Chen, G., Li, X., Huang, M., Li, M., Zhou, X., Li, Y. and Bai, J. (2016) Thioredoxin-1 increases survival in sepsis by inflammatory response through suppressing endoplasmic reticulum stress. Shock 46, 67-74. https://doi.org/10.1097/SHK.0000000000000570
  2. Cohen, J. I., Roychowdhury, S., DiBello, P. M., Jacobsen, D. W. and Nagy, L. E. (2009) Exogenous thioredoxin prevents ethanol-induced oxidative damage and apoptosis in mouse liver. Hepatology 49, 1709-1717. https://doi.org/10.1002/hep.22837
  3. Cuadrado, A. and Nebreda, A. R. (2010) Mechanisms and functions of p38 MAPK signalling. Biochem. J. 429, 403-417.
  4. D'Annunzio, V., Perez, V., Boveris, A., Gelpi, R. J. and Poderoso, J. J. (2016) Role of thioredoxin-1 in ischemic preconditioning, postconditioning and aged ischemic hearts. Pharmacol. Res. 109, 24-31. https://doi.org/10.1016/j.phrs.2016.03.009
  5. Dai, M. X., Zheng, X. H., Yu, J., Yin, T., Ma, M. J., Zhang, L., Liu, M., Ma, Y., Liu, L. W., Gao, X., Li, Y., Song, L. Q. and Wang, H. C. (2014) The impact of intermittent and repetitive cold stress exposure on endoplasmic reticulum stress and instability of atherosclerotic plaques. Cell. Physiol. Biochem. 34, 393-404. https://doi.org/10.1159/000363008
  6. Dunn, S., Vohra, R. S., Murphy, J. E., Homer-Vanniasinkam, S., Walker, J. H. and Ponnambalam, S. (2008) The lectin-like oxidized low-density-lipoprotein receptor: a pro-inflammatory factor in vascular disease. Biochem. J. 409, 349-355. https://doi.org/10.1042/BJ20071196
  7. Gleissner, C. A. (2016) Translational atherosclerosis research: from experimental models to coronary artery disease in humans. Atherosclerosis 248, 110-116. https://doi.org/10.1016/j.atherosclerosis.2016.03.013
  8. Guo, R., Su, Y., Liu, B., Li, S., Zhou, S. and Xu, Y. (2014) Resveratrol suppresses oxidised low-density lipoprotein-induced macrophage apoptosis through inhibition of intracellular reactive oxygen species generation, LOX-1, and the p38 MAPK pathway. Cell. Physiol. Biochem. 34, 603-616.
  9. Holmgren, A. (1985) Thioredoxin. Annu. Rev. Biochem. 54, 237-271. https://doi.org/10.1146/annurev.bi.54.070185.001321
  10. Hsieh, C. C. and Papaconstantinou, J. (2006) Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. FASEB J. 20, 259-268. https://doi.org/10.1096/fj.05-4376com
  11. Inoue, K., Arai, Y., Kurihara, H., Kita, T. and Sawamura, T. (2005) Over-expression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice. Circ. Res. 97, 176-184. https://doi.org/10.1161/01.RES.0000174286.73200.d4
  12. Ishiyama, J., Taguchi, R., Yamamoto, A. and Murakami, K. (2010) Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells. Atherosclerosis 209, 118-124. https://doi.org/10.1016/j.atherosclerosis.2009.09.004
  13. Janicke, R. U., Sprengart, M. L., Wati, M. R. and Porter, A. G. (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem. 273, 9357-9360. https://doi.org/10.1074/jbc.273.16.9357
  14. Kamimoto, Y., Sugiyama, T., Kihira, T., Zhang, L., Murabayashi, N., Umekawa, T., Nagao, K., Ma, N., Toyoda, N., Yodoi, J. and Sagawa, N. (2010) Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy. Diabetologia 53, 2046-2055. https://doi.org/10.1007/s00125-010-1784-y
  15. Kataoka, H., Kume, N., Miyamoto, S., Minami, M., Moriwaki, H., Murase, T., Sawamura, T., Masaki, T., Hashimoto, N. and Kita, T. (1999) Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation 99, 3110-3117. https://doi.org/10.1161/01.CIR.99.24.3110
  16. Laurent, T. C., Moore, E. C. and Reichard, P. (1964) Enzymatic synthesis of deoxyribonucleotides. IV. Isolation and characterization of thioredoxin, the hydrogen donor from escherichia coli B. J. Biol. Chem. 239, 3436-3444.
  17. Liao, X., Sluimer, J. C., Wang, Y., Subramanian, M., Brown, K., Pattison, J. S., Robbins, J., Martinez, J. and Tabas, I. (2012) Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15, 545-553. https://doi.org/10.1016/j.cmet.2012.01.022
  18. Lin, Y. W., Liu, P. S., Adhikari, N., Hall, J. L. and Wei, L. N. (2015) RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. J. Mol. Cell. Cardiol. 79, 287-294. https://doi.org/10.1016/j.yjmcc.2014.12.009
  19. Luo, Y., Sun, G., Dong, X., Wang, M., Qin, M., Yu, Y. and Sun, X. (2015) Isorhamnetin attenuates atherosclerosis by inhibiting macrophage apoptosis via PI3K/AKT activation and HO-1 induction. PLoS ONE 10, e0120259. https://doi.org/10.1371/journal.pone.0120259
  20. Matsui, M., Oshima, M., Oshima, H., Takaku, K., Maruyama, T., Yodoi, J. and Taketo, M. M. (1996) Early embryonic lethality caused by targeted disruption of the mouse thioredoxin gene. Dev. Biol. 178, 179-185. https://doi.org/10.1006/dbio.1996.0208
  21. Mehta, J. L., Sanada, N., Hu, C. P., Chen, J., Dandapat, A., Sugawara, F., Satoh, H., Inoue, K., Kawase, Y., Jishage, K., Suzuki, H., Takeya, M., Schnackenberg, L., Beger, R., Hermonat, P. L., Thomas, M. and Sawamura, T. (2007) Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. Circ. Res. 100, 1634-1642. https://doi.org/10.1161/CIRCRESAHA.107.149724
  22. Moore, K. J., Sheedy, F. J. and Fisher, E. A. (2013) Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709-721. https://doi.org/10.1038/nri3520
  23. Moore, K. J. and Tabas, I. (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145, 341-355. https://doi.org/10.1016/j.cell.2011.04.005
  24. Pirillo, A., Norata, G. D. and Catapano, A. L. (2013) LOX-1, OxLDL, and atherosclerosis. Mediators Inflamm. 2013, 152786.
  25. Powis, G. and Montfort, W. R. (2001) Properties and biological activities of thioredoxins. Annu. Rev. Biophys. Biomol. Struct. 30, 421-455. https://doi.org/10.1146/annurev.biophys.30.1.421
  26. Rusinol, A. E., Thewke, D., Liu, J., Freeman, N., Panini, S. R. and Sinensky, M. S. (2004) AKT/protein kinase B regulation of BCL family members during oxysterol-induced apoptosis. J. Biol. Chem. 279, 1392-1399. https://doi.org/10.1074/jbc.M308619200
  27. Saitoh, M., Nishitoh, H., Fujii, M., Takeda, K., Tobiume, K., Sawada, Y., Kawabata, M., Miyazono, K. and Ichijo, H. (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17, 2596-2606. https://doi.org/10.1093/emboj/17.9.2596
  28. Schaeffer, D. F., Riazy, M., Parhar, K. S., Chen, J. H., Duronio, V., Sawamura, T. and Steinbrecher, U. P. (2009) LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasma. J. Lipid Res. 50, 1676-1684.
  29. Seimon, T. and Tabas, I. (2009) Mechanisms and consequences of macrophage apoptosis in atherosclerosis. J. Lipid Res. 50 Suppl, S382-S387. https://doi.org/10.1194/jlr.R800032-JLR200
  30. 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
  31. Tabas, I. (2010) Macrophage death and defective inflammation resolution in atherosclerosis. Nat. Rev. Immunol. 10, 36-46. https://doi.org/10.1038/nri2675
  32. Tao, L., Gao, E., Hu, A., Coletti, C., Wang, Y., Christopher, T. A., Lopez, B. L., Koch, W. and Ma, X. L. (2006) Thioredoxin reduces post-ischemic myocardial apoptosis by reducing oxidative/nitrative stress. Br. J. Pharmacol. 149, 311-318. https://doi.org/10.1038/sj.bjp.0706853
  33. Wang, B., Tian, S., Wang, J., Han, F., Zhao, L., Wang, R., Ning, W., Chen, W. and Qu, Y. (2015) Intraperitoneal administration of thioredoxin decreases brain damage from ischemic stroke. Brain Res. 1615, 89-97. https://doi.org/10.1016/j.brainres.2015.04.033
  34. Wang, W. L., Meng, Z. X., Zhou, S. J., Li, C. J., Chen, R., Lv, L., Ma, Z. J., Yu, D. M. and Yu, P. (2013) Reduced beta2-glycoprotein I protects macrophages from ox-LDL-induced foam cell formation and cell apoptosis. Lipids Health Dis. 12, 174. https://doi.org/10.1186/1476-511X-12-174
  35. Xia, X., Li, Y., Su, Q., Huang, Z., Shen, Y., Li, W. and Yu, C. (2015) Inhibitory effects of Mycoepoxydiene on macrophage foam cell formation and atherosclerosis in ApoE-deficient mice. Cell Biosci. 5, 23. https://doi.org/10.1186/s13578-015-0017-y
  36. Yamawaki, H., Haendeler, J. and Berk, B. C. (2003) Thioredoxin: a key regulator of cardiovascular homeostasis. Circ. Res. 93, 1029-1033. https://doi.org/10.1161/01.RES.0000102869.39150.23
  37. Yoshimoto, R., Fujita, Y., Kakino, A., Iwamoto, S., Takaya, T. and Sawamura, T. (2011) The discovery of LOX-1, its ligands and clinical significance. Cardiovasc. Drugs Ther. 25, 379-391. https://doi.org/10.1007/s10557-011-6324-6

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