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Kimchi suppresses 7-ketocholesterol-induced endoplasmic reticulum stress in macrophages

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Abstract

The oxidation of low-density lipoproteins (oxLDL) is considered as a key step in the development of atherosclerosis. Oxysterols such as 7-ketocholesterol (7-KC) have been reported to be partially responsible for the cytotoxicity of oxLDL and induce endoplasmic reticulum (ER) stress which eventually causes apoptosis. We aimed to investigate whether ER stress is induced by 7-KC and can be prevented by the kimchi methanol extract (KME) in RAW264.7 macrophage cells. ER stress induced by 7-KC was characterized by the activation of ER stress markers (GRP78, CHOP, and ATF6). ER stress could aggravate macrophage apoptosis, as assessed by caspase-3 activity. ER stress and apoptosis were inhibited by the KME and glutathione (GSH). We conclude that 7-KC causes aberrant ER stress and apoptosis, all of which are inhibited by KME and GSH. The inhibitory expression of ER stress markers highlights its new protective role against oxLDL-induced ER stress, apoptosis, and subsequent atherosclerosis.

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References

  1. Austin RC. The unfolded protein response in health and disease. Antioxid. Redox Sign. 11: 2279–2287 (2009)

    Article  CAS  Google Scholar 

  2. Tabas I. The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ. Res. 107: 839–850 (2010)

    Article  CAS  Google Scholar 

  3. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature 454: 455–462 (2008)

    Article  CAS  Google Scholar 

  4. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Bio. 8: 519–529 (2007)

    Article  CAS  Google Scholar 

  5. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu. Rev. Biochem. 74: 739–789 (2005)

    Article  Google Scholar 

  6. Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, Asada Y, Okada K, Ishibashi-Ueda H, Gabbiani G, Bochaton-Piallat ML, Mochizuki N, Kitakaze M. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116: 1226–1233 (2007)

    Article  Google Scholar 

  7. Sanson M, Auge N, Vindis C, Muller C, Bando Y, Thiers JC, Marachet MA, Zarkovic K, Sawa Y, Salvayre R, Negre-Salvayre A. Oxidized low-density lipoproteins trigger endoplasmic reticulum stress in vascular cells: Prevention by oxygen-regulated protein 150 expression. Circ. Res. 104: 328–336 (2009)

    Article  CAS  Google Scholar 

  8. Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities. Nature Rev. 7: 1013–1030 (2008)

    Article  CAS  Google Scholar 

  9. Ross A. Atherosclerosis: An inflammatory disease. New Engl. J. Med. 340: 115–126 (1999)

    Article  CAS  Google Scholar 

  10. Hayden JM, Brachova L, Higgins K, Obermiller L, Sevanian A, Khandrika S, Reaven PD. Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol. J. Lipid Res. 43: 26–35 (2002)

    CAS  Google Scholar 

  11. Lizard GM, Moisant M, Cordelet C, Monier S, Gambert P, Lagrost L. Induction of similar features of apoptosis in human and bovine vascular endothelial cells treated by 7-ketocholesterol. J. Pathol. 183: 330–338 (1997)

    Article  CAS  Google Scholar 

  12. Miyashita YK, Shirai K, Ito Y, Watanabe J, Urano Y, Murano T, Tomioka H. Cytotoxicity of some oxysterols on human vascular smooth muscle cells was mediated by apoptosis. J. Atheroscler. Thromb. 4: 73–78 (1997)

    CAS  Google Scholar 

  13. Lemaire S, Lizard G, Monier S, Miguet C, Gueldry S, Volot F, Gambert P, Neel D. Different patterns of IL-1β secretion, adhesion molecule expression, and apoptosis induction in human endothelial cells treated with 7α-, 7β-hydroxycholesterol, or 7-ketocholesterol. FEBS Lett. 440: 434–439 (1998)

    Article  CAS  Google Scholar 

  14. Gelissen IC, Brown AJ, Mander EL, Kritharides L, Dean RT, Jessup W. Sterol efflux is impaired from macrophage foam cells selectively enriched with 7-ketocholesterol. J. Biol. Chem. 271: 17852–17860 (1996)

    Article  CAS  Google Scholar 

  15. Cheigh HS, Park KY. Biochemical, microbiological, and nutritional aspects of kimchi (Korean fermented vegetable products). Crit. Rev. Food Sci. 34: 175–203 (1995)

    Article  Google Scholar 

  16. Song YO. The functional properties of kimchi for the health benefits. Food Ind. Nutr. 9: 27–33 (2004)

    Google Scholar 

  17. Sheo HJ, Seo YS. The effects of dietary Chinese cabbage kimchi juice on the lipid metabolism and body weight gain in rats fed high-caloriesdiet. J. Korean Soc. Food Sci. Nutr. 33: 91–100 (2004)

    Article  CAS  Google Scholar 

  18. Park KY, Cheigh HS. Antimutagenic and anticancer effects of lactic acid bacteria isolated from kimchi. Bioindus. News 13: 84–90 (2000)

    Google Scholar 

  19. Lee YM, Kwon MJ, Kim JK, Suh HS, Choi JS, Song YO. Isolation and identification of active principle in Chinese cabbage kimchi responsible for antioxidant effect. J. Korean Soc. Food Sci. Nutr. 36: 129–133 (2004)

    Google Scholar 

  20. Kim HJ, Lee JS, Chung HY, Song SH, Suh H, Noh JS, Song YO. 3-(4′-Hydroxyl-3′,5′-dimethoxyphenyl)propionic acid, an active principle of kimchi, inhibits development of atherosclerosis in rabbits. J. Agr. Food Chem. 55: 10486–10492 (2007)

    Article  CAS  Google Scholar 

  21. Noh JS, Kim HJ, Kwon MJ, Song YO. Active principle of kimchi, 3-(4′-hydroxyl-3′, 5′-dimethoxyphenyl)propionic acid, retards fatty streak formation at aortic sinus of apolipoprotein E knockout mice. J. Med. Food 12: 1206–1212 (2009)

    Article  CAS  Google Scholar 

  22. Cho EJ, Lee SM, Rhee SH, Park KY. Studies on the standardization of Chinese cabbage kimchi. Korean J. Food Sci. Technol. 30: 324–332 (1998)

    Google Scholar 

  23. Leonarduzzi G, Chiarpotto E, Biasi F, Poli G. 4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis. Mol. Nutr. Food Res. 49: 1044–1049 (2005)

    Article  CAS  Google Scholar 

  24. Napoli C. Oxidation of LDL, atherogenesis, and apoptosis. Ann. NY Acad. Sci. 1010: 698–709 (2003)

    Article  CAS  Google Scholar 

  25. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword? Antioxid. Redox Sign. 9: 2277–2293 (2007)

    Article  CAS  Google Scholar 

  26. Brown AJ, Jessup W. Oxysterols and atherosclerosis. Atherosclerosis 142: 1–28 (1999)

    Article  CAS  Google Scholar 

  27. Zhou J, Werstuck GH, Lhotak S, de Koning AB, Sood SK, Hossain GS, Moller J, Ritskes-Hoitinga M, Falk E, Dayal S, Lentz SR, Austin RC. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyper homocysteinemic apolipoprotein E-deficient mice. Circulation 110: 207–213 (2004)

    Article  CAS  Google Scholar 

  28. Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, Sweeney M, Rong JX, Kuriakose G, Fisher, EA, Marks AR, Ron D, Tabas I. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat. Cell Biol. 5: 781–792 (2003)

    Article  CAS  Google Scholar 

  29. Zhou J, Lhotak S, Hilditch BA, Austin RC. Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation 111: 1814–1821 (2005)

    Article  CAS  Google Scholar 

  30. Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of ApoE-/- and LDLr-/- mice lacking CHOP. Cell Metab. 9: 474–481 (2009)

    Article  CAS  Google Scholar 

  31. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell. 11: 619–633 (2003)

    Article  CAS  Google Scholar 

  32. Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat. Cell Biol. 3: E255–E263 (2001)

    Article  CAS  Google Scholar 

  33. Malhotra JD, Miao H, Zhang K, Wolfson A, Pennathur S, Pipe SW, Kaufman RJ. Antioxidnats reduce endoplasmic reticulum stress and improve protein secretion. P. Natl. Acad. Sci. USA 105: 18525–18530 (2008)

    Article  CAS  Google Scholar 

  34. Zhao L, Ackerman SL. Endoplasmic reticulum stress in health and disease. Curr. Opin. Cell Biol. 18: 444–452 (2006)

    Article  CAS  Google Scholar 

  35. Blais JD, Chin KT, Zito E, Zhang Y, Heldman N, Harding HP, Fass D, Thorpe C, Ron D. A small molecule inhibitor of endoplasmic reticulum oxidation 1 (ERO1) with selectively reversible thiol reactivity. J. Biol. Chem. 285: 20993–21003 (2010)

    Article  CAS  Google Scholar 

  36. Pedruzzi E, Guichard C, Ollivier V, Driss F, Fay M, Prunet C, Marie JC, Pouzet C, Samadi M, Elbim C, O’dowd Y, Bens M, Vandewalle A, Gougerot-Pocidalo MA, Lizard G, Ogier-Denis E. NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol. Cell. Biol. 24: 10703–10717 (2004)

    Article  CAS  Google Scholar 

  37. Devries-Seimon T, Li Y, Yao PM, Stone E, Wang Y, Davis RJ, Flavell R, Tabas I. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J. Cell Biol. 171: 61–73 (2005)

    Article  CAS  Google Scholar 

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Correspondence to Hyun Ju Kim.

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Kim, H.J., Sung, Y.B., Song, YO. et al. Kimchi suppresses 7-ketocholesterol-induced endoplasmic reticulum stress in macrophages. Food Sci Biotechnol 21, 1293–1299 (2012). https://doi.org/10.1007/s10068-012-0170-6

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  • DOI: https://doi.org/10.1007/s10068-012-0170-6

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