European Journal of Nutrition

, Volume 49, Issue 2, pp 119–126 | Cite as

Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages

  • Yoshimi Kishimoto
  • Mariko Tani
  • Harumi Uto-Kondo
  • Maki Iizuka
  • Emi Saita
  • Hirohito Sone
  • Hideaki Kurata
  • Kazuo KondoEmail author
Original Contribution



Astaxanthin is a red carotenoid pigment which has significant potential for antioxidant activity. The macrophages in atherosclerotic lesions, known as activated macrophages, express scavenger receptors responsible for the clearance of pathogenic lipoproteins. In addition, the expression and secretion of proteolytic enzymes, matrix metalloproteinases (MMPs), and pro-inflammatory cytokines are remarkably promoted in activated macrophages.

Aim of the study

In this study, we investigated the effects of astaxanthin on the expression of scavenger receptors, MMPs, and pro-inflammatory cytokines in macrophages.


THP-1 macrophages were incubated with 5–10 μM astaxanthin for 24 h. The expression levels of scavenger receptors, MMPs, and pro-inflammatory cytokines were determined by Western blot analysis or real-time RT-PCR. The MMP-9 and -2 activities were examined by gelatin zymography and total MMP activity was measured by fluorometry.


We found that astaxanthin remarkably decreased the class A scavenger receptor and CD36 expression in the protein and mRNA levels. Astaxanthin also reduced MMP-1, -2, -3, -9, -12, and -14 activity and expression. The mRNA expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 were significantly suppressed by astaxanthin. Furthermore, astaxanthin inhibited the phosphorylation of nuclear factor-κB.


These results indicate that astaxanthin has inhibitory effects on macrophage activation, such as scavenger receptors up-regulation, MMPs activation, and pro-inflammatory cytokines secretion.


Astaxanthin Macrophage Scavenger receptor Matrix metalloproteinase Atherosclerosis 



This study was supported in part by Grant-in-Aid (20300244 to K. K.) from the Japan Society for the Promotion of Science. Y. K. is supported by research fellowships of the Japan Society for the Promotion of Science for young scientists. We thank Fuji Chemical Industry Co., Ltd for supplying the astaxanthin.

Conflict of interest statement

We have no conflict of interest.


  1. 1.
    Baeuerle PA, Baltimore D (1996) NF-kappa B: ten years after. Cell 87:13–20CrossRefGoogle Scholar
  2. 2.
    Chakraborti S, Mandal M, Das S, Mandal A, Chakraborti T (2003) Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 253:269–285CrossRefGoogle Scholar
  3. 3.
    Chase AJ, Bond M, Crook MF, Newby AC (2002) Role of nuclear factor-kappa B activation in metalloproteinase-1, -3, and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo. Arterioscler Thromb Vasc Biol 22:765–771CrossRefGoogle Scholar
  4. 4.
    Chen F, Eriksson P, Hansson GK, Herzfeld I, Klein M, Hansson LO, Valen G (2005) Expression of matrix metalloproteinase 9 and its regulators in the unstable coronary atherosclerotic plaque. Int J Mol Med 15:57–65Google Scholar
  5. 5.
    Chew BP, Park JS, Wong MW, Wong TS (1999) A comparison of the anticancer activities of dietary beta-carotene, canthaxanthin and astaxanthin in mice in vivo. Anticancer Res 19:1849–1853Google Scholar
  6. 6.
    De Waart FG, Schouten EG, Stalenhoef AF, Kok FJ (2001) Serum carotenoids, alpha-tocopherol and mortality risk in a prospective study among Dutch elderly. Int J Epidemiol 30:136–143CrossRefGoogle Scholar
  7. 7.
    Devaraj S, Hugou I, Jialal I (2001) Alpha-tocopherol decreases CD36 expression in human monocyte-derived macrophages. J Lipid Res 42:521–527Google Scholar
  8. 8.
    Eguchi A, Murakami A, Ohigashi H (2006) Nobiletin, a citrus flavonoid, suppresses phorbol ester-induced expression of multiple scavenger receptor genes in THP-1 human monocytic cells. FEBS Lett 580:3321–3328CrossRefGoogle Scholar
  9. 9.
    Evans RW, Shaten BJ, Day BW, Kuller LH (1998) Prospective association between lipid soluble antioxidants and coronary heart disease in men. The multiple risk factor intervention trial. Am J Epidemiol 147:180–186Google Scholar
  10. 10.
    Fukuhara-Takaki K, Sakai M, Sakamoto Y, Takeya M, Horiuchi S (2005) Expression of class A scavenger receptor is enhanced by high glucose in vitro and under diabetic conditions in vivo: one mechanism for an increased rate of atherosclerosis in diabetes. J Biol Chem 280:3355–3364CrossRefGoogle Scholar
  11. 11.
    Fukuzawa K, Inokami Y, Tokumura A, Terao J, Suzuki A (1998) Rate constants for quenching singlet oxygen and activities for inhibiting lipid peroxidation of carotenoids and alpha-tocopherol in liposomes. Lipids 33:751–756CrossRefGoogle Scholar
  12. 12.
    Galis ZS, Asanuma K, Godin D, Meng X (1998) N-acetyl-cysteine decreases the matrix-degrading capacity of macrophage-derived foam cells: new target for antioxidant therapy? Circulation 97:2445–2453Google Scholar
  13. 13.
    Giansante C, Fiotti N, Di Chiara A, Altamura N, Wasserman S, Fioretti P, Guarnieri G (2007) In-hospital outcome of patients with acute coronary syndrome: relationship with inflammation and remodeling markers. J Cardiovasc Med (Hagerstown) 8:602–607Google Scholar
  14. 14.
    Goto S, Kogure K, Abe K, Kimata Y, Kitahama K, Yamashita E, Terada H (2001) Efficient radical trapping at the surface and inside the phospholipid membrane is responsible for highly potent antiperoxidative activity of the carotenoid astaxanthin. Biochim Biophys Acta 1512:251–258CrossRefGoogle Scholar
  15. 15.
    Gross GJ, Lockwood SF (2005) Acute and chronic administration of disodium disuccinate astaxanthin (Cardax) produces marked cardioprotection in dog hearts. Mol Cell Biochem 272:221–227CrossRefGoogle Scholar
  16. 16.
    Gross GJ, Lockwood SF (2004) Cardioprotection and myocardial salvage by a disodium disuccinate astaxanthin derivative (Cardax). Life Sci 75:215–224CrossRefGoogle Scholar
  17. 17.
    Inokubo Y, Hanada H, Ishizaka H, Fukushi T, Kamada T, Okumura K (2001) Plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 are increased in the coronary circulation in patients with acute coronary syndrome. Am Heart J 141:211–217CrossRefGoogle Scholar
  18. 18.
    Iwamoto T, Hosoda K, Hirano R, Kurata H, Matsumoto A, Miki W, Kamiyama M, Itakura H, Yamamoto S, Kondo K (2000) Inhibition of low-density lipoprotein oxidation by astaxanthin. J Atheroscler Thromb 7:216–222Google Scholar
  19. 19.
    Jacobsson LS, Yuan XM, Zieden B, Olsson AG (2004) Effects of alpha-tocopherol and astaxanthin on LDL oxidation and atherosclerosis in WHHL rabbits. Atherosclerosis 173:231–237Google Scholar
  20. 20.
    Jung WJ, Sung MK (2004) Effects of major dietary antioxidants on inflammatory markers of RAW 264.7 macrophages. Biofactors (Oxford) 21:113–117CrossRefGoogle Scholar
  21. 21.
    Jyonouchi H, Sun S, Iijima K, Gross MD (2000) Antitumor activity of astaxanthin and its mode of action. Nutr Cancer 36:59–65CrossRefGoogle Scholar
  22. 22.
    Kawai Y, Nishikawa T, Shiba Y, Saito S, Murota K, Shibata N, Kobayashi M, Kanayama M, Uchida K, Terao J (2008) Macrophage as a target of quercetin glucuronides in human atherosclerotic arteries: implication in the anti-atherosclerotic mechanism of dietary flavonoids. J Biol Chem 283:9424–9434CrossRefGoogle Scholar
  23. 23.
    Kim GY, Kim JH, Ahn SC, Lee HJ, Moon DO, Lee CM, Park YM (2004) Lycopene suppresses the lipopolysaccharide-induced phenotypic and functional maturation of murine dendritic cells through inhibition of mitogen-activated protein kinases and nuclear factor-kappaB. Immunology 113:203–211CrossRefGoogle Scholar
  24. 24.
    Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, Rhee JS, Silverstein R, Hoff HF, Freeman MW (2002) Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem 277:49982–49988CrossRefGoogle Scholar
  25. 25.
    Lauver DA, Driscoll EM, Lucchesi BR (2008) Disodium disuccinate astaxanthin prevents carotid artery rethrombosis and ex vivo platelet activation. Pharmacology 82:67–73CrossRefGoogle Scholar
  26. 26.
    Lendon CL, Davies MJ, Born GV, Richardson PD (1991) Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis 87:87–90CrossRefGoogle Scholar
  27. 27.
    Liao YF, Hung HC, Hsu PC, Kao MC, Hour TC, Tsay GJ, Liu GY (2008) Ornithine decarboxylase interferes with macrophage-like differentiation and matrix metalloproteinase-9 expression by tumor necrosis factor alpha via NF-kappaB. Leuk Res 32:1124–1140CrossRefGoogle Scholar
  28. 28.
    Mamputu JC, Li L, Renier G (2006) Gliclazide inhibits differentiation-associated biologic events in human monocyte-derived macrophages. Metab Clin Exp 55:778–785Google Scholar
  29. 29.
    Miller YI, Chang MK, Binder CJ, Shaw PX, Witztum JL (2003) Oxidized low density lipoprotein and innate immune receptors. Curr Opin Lipidol 14:437–445CrossRefGoogle Scholar
  30. 30.
    Murr C, Winklhofer-Roob BM, Schroecksnadel K, Maritschnegg M, Mangge H, Bohm BO, Winkelmann BR, Marz W, Fuchs D (2009) Inverse association between serum concentrations of neopterin and antioxidants in patients with and without angiographic coronary artery disease. Atherosclerosis 202:543–549CrossRefGoogle Scholar
  31. 31.
    Naguib YM (2000) Antioxidant activities of astaxanthin and related carotenoids. J Agric Food Chem 48:1150–1154CrossRefGoogle Scholar
  32. 32.
    Newby AC (2008) Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol 28:2108–2114CrossRefGoogle Scholar
  33. 33.
    Ozer NK, Negis Y, Aytan N, Villacorta L, Ricciarelli R, Zingg JM, Azzi A (2006) Vitamin E inhibits CD36 scavenger receptor expression in hypercholesterolemic rabbits. Atherosclerosis 184:15–20CrossRefGoogle Scholar
  34. 34.
    Palozza P, Serini S, Torsello A, Di Nicuolo F, Piccioni E, Ubaldi V, Pioli C, Wolf FI, Calviello G (2003) Beta-carotene regulates NF-kappaB DNA-binding activity by a redox mechanism in human leukemia and colon adenocarcinoma cells. J Nutr 133:381–388Google Scholar
  35. 35.
    Ross R (1999) Atherosclerosis is an inflammatory disease. Am Heart J 138:S419–S420CrossRefGoogle Scholar
  36. 36.
    Singh U, Devaraj S, Jialal I (2005) Vitamin E, oxidative stress, and inflammation. Annu Rev Nutr 25:151–174CrossRefGoogle Scholar
  37. 37.
    Vaday GG, Franitza S, Schor H, Hecht I, Brill A, Cahalon L, Hershkoviz R, Lider O (2001) Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix. J Leukoc Biol 69:885–892Google Scholar
  38. 38.
    Walrand S, Farges MC, Dehaese O, Cardinault N, Minet-Quinard R, Grolier P, Bouteloup-Demange C, Ribalta J, Winklhofer-Roob BM, Rock E, Vasson MP (2005) In vivo and in vitro evidences that carotenoids could modulate the neutrophil respiratory burst during dietary manipulation. Eur J Nutr 44:114–120CrossRefGoogle Scholar
  39. 39.
    Watanabe N, Ikeda U (2004) Matrix metalloproteinases and atherosclerosis. Curr Atheroscler Rep 6:112–120CrossRefGoogle Scholar
  40. 40.
    Woo JH, Park JW, Lee SH, Kim YH, Lee IK, Gabrielson E, Lee SH, Lee HJ, Kho YH, Kwon TK (2003) Dykellic acid inhibits phorbol myristate acetate-induced matrix metalloproteinase-9 expression by inhibiting nuclear factor kappa B transcriptional activity. Cancer Res 63:3430–3434Google Scholar
  41. 41.
    Zeng B, Prasan A, Fung KC, Solanki V, Bruce D, Freedman SB, Brieger D (2005) Elevated circulating levels of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease. Intern Med J 35:331–335CrossRefGoogle Scholar
  42. 42.
    Zhou M, Zhang Y, Ardans JA, Wahl LM (2003) Interferon-gamma differentially regulates monocyte matrix metalloproteinase-1 and -9 through tumor necrosis factor-alpha and caspase 8. J Biol Chem 278:45406–45413CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Yoshimi Kishimoto
    • 1
  • Mariko Tani
    • 1
  • Harumi Uto-Kondo
    • 2
  • Maki Iizuka
    • 1
  • Emi Saita
    • 1
  • Hirohito Sone
    • 3
  • Hideaki Kurata
    • 4
  • Kazuo Kondo
    • 1
    Email author
  1. 1.Institute of Environmental Science for Human LifeOchanomizu UniversityTokyoJapan
  2. 2.Internal Medicine 1National Defense Medical CollegeTokorozawaJapan
  3. 3.Department of Lifestyle Medicine and Applied NutritionOchanomizu UniversityTokyoJapan
  4. 4.Division of Diabetes Metabolism and Endocrinology, Department of Internal MedicineJikei University School of MedicineTokyoJapan

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