Lipids

, Volume 41, Issue 7, pp 655–662 | Cite as

Soy protein containing isoflavones favorably influences macrophage lipoprotein metabolism but not the development of atherosclerosis in CETP transgenic mice

  • Leiko Asakura
  • Patrícia M. Cazita
  • Lila M. Harada
  • Valéria S. Nunes
  • Jairo A. Berti
  • Alessandro G. Salerno
  • Daniel F. J. Ketelhuth
  • Magnus Gidlund
  • Helena C. F. Oliveria
  • Eder C. R. Quintão
Articles

Abstract

The possibility that soy protein containing isoflavones influences the development of experimental atherosclerosis has been investigated in ovariectomized mice heterozygous for the human CETP transgene and for the LDL-receptor null allele (LDLr+/− CETP+/−). After ovariectomy at 8 wk of age they were fed a fat/cholesterol-rich diet for 19 wk and divided into three experimental groups: dietary unmodified soy protein containing isoflavones (mg/g of diet), either at low-dose (Iso Low, 0.272, n=25), or at high-dose (Iso High, 0.535, n=28); and the atherogenic diet containing an isoflavone-depleted alcohol-washed soy protein as a control group (n=28). Aortic root lipid-stained lesion area (mean μm2×103±SD) did not differ among Iso Low (12.3±9.9), Iso High (7.4±6.4), and controls (10.7±12.8). Autoantibody titers against plasma oxidized LDL did not differ among the experimental groups. Using the control mice as the reference value (100%), in vitro mouse peritoneal macrophage uptake of labeled acetylated LDL-cholesterol was lower in the Iso High (68%) than in the Iso Low (85%) group. The in vitro percent removal by exogenous HDL of labeled unesterified cholesterol from macrophages previously enriched with human [4-14C]-cholesteryl oleate acetylated LDL was enhanced in the Iso High group (50%). In spite of these in vitro potentially antiatherogenic actions, soy protein containing isoflavones did not modify the average size of lipid-stained area in the aortic root.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Grady, D., Herrington, D., Bittner, V., Blumenthal, R., Davidson, M., Hlatky, M., Hsia, J., Hulley, S., Herd, A., Khan, S., Newby, L.K., Waters, D., Vittinghoff, E., and Wenger, N. (2002) HERS Research Group. Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II), JAMA 288, 49–57.PubMedCrossRefGoogle Scholar
  2. 2.
    Hulley, S., Furberg, C., Barrett-Connor, E., Cauley, J., Grady, D., Haskell, W., Knopp, R., Lowery, M., Satterfield, S., Schrott, H., Vittinghoff, E., and Hunninghake, D. (2002) HERS Research Group. Noncardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II), JAMA 288, 58–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Writing Group for the Women's Health Initiative Investigators. (2002) Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women's Health Initiative Randomized Controlled Trial, JAMA 288, 321–333.CrossRefGoogle Scholar
  4. 4.
    Zhuo, X.G., Melby, M.K., and Watanabe, S. (2004) Soy Isoflavone Intake Lowers Serum LDL Cholesterol: A Meta-analysis of Eight Randomized Controlled Trials in Humans, J. Nutr. 134, 2395–2400.PubMedGoogle Scholar
  5. 5.
    Albertazzi, P., Pansini, F., Bonaccorsi, G., Zanotti, L., Forini, E., and De Aloysio, D. (1998) The Effect of Dietary Soy Supplementation on Hot Flushes, Obstet. Gynecol. 91, 96–11.CrossRefGoogle Scholar
  6. 6.
    Crisafulli, A., Marini, H., Bitto, A., Altavilla, D., Squadrito, G., Romeo, A., Adamo, E.B., Marini, R., D'Anna, R., Corrado, F., Bartolone, S., Frisina, N., and Squadrito, F. (2004) Effects of Genistein on Hot Flushes in Early Postmenopausal Women: A Randomized, Double-Blind EPT- and Placebo-Controlled Study. Menopause 11, 400–404.PubMedCrossRefGoogle Scholar
  7. 7.
    Horiuchi, T., Onouchi, T., Takahashi, M., Ito, H., and Orimo, H. (2000) Effect of Soy Protein on Bone Metabolism in Postmenopausal Japanese Women, Osteoporos. Int. 11, 721–724.PubMedCrossRefGoogle Scholar
  8. 8.
    Cassidy, A., and Griffin, B. (1999) Phyto-oestrogens: A Potential Role in the Prevention of CHD? Proc. Nutr. Soc. 58, 193–199.PubMedCrossRefGoogle Scholar
  9. 9.
    Vitolins, M.Z., Anthony, M., and Burke, G.L. (2001) Soy Protein Isoflavones, Lipids and Arterial Disease, Curr. Opin. Lipidol. 12, 437–437.CrossRefGoogle Scholar
  10. 10.
    Sacks, F.M., Lichtenstein, A., Van Horn, L., Harris, W., Kris-Etherton, P., and Winston, M. American Heart Association Nutrition Committee. (2006) Soy Protein, Isoflavones, and Cardiovascular Health: An American Heart Association Science Advisory for Professionals from the Nutrition Committee, Circulation 113, 1034–1044.PubMedCrossRefGoogle Scholar
  11. 11.
    Van der Schouw, Y.T., Kreijkamp-Kaspers, S., Peeters, P.H., Keinan-Boker, L., Rimm, E.B., and Grobee, D.E. (2005) Prospective Study on Usual Dietary Phytoestrogen Intake and Cardiovascular Disease Risk in Western Women, Circulation 111, 466–471.CrossRefGoogle Scholar
  12. 12.
    Clarkson, T.B. (2002) Soy, Soy Phytoestrogens and Cardiovascular Disease, J. Nutr. 132, 66S-569S.Google Scholar
  13. 13.
    Anderson, J.W., Johnsotone, B.M., and Cook-Newell, M.E. (1995) Meta-analysis of the Effects of Soy Protein Intake on Serum Lipids, N. Engl. J. Med. 333, 276–282.PubMedCrossRefGoogle Scholar
  14. 14.
    Engelman, H.M., Alekel, D.L., Hanson, L.N., Kanthasamy, A.G., and Reddy, M.B. (2005) Blood Lipid and Oxidative Stress Responses to Soy Protein with Isoflavones and Phytic Acid in Postmenopausal Women, Am. J. Clin. Nutr. 81, 590–596.PubMedGoogle Scholar
  15. 15.
    Kreijkamp-Kaspers, S., Kok, L., Grobbee, D.E., de Haan, E.H., Aleman, A., Lampe, J.W., and Van der Schouw, Y.T. (2004) Effect of Soy Protein Containing Isoflavones on Cognitive Function, Bone Mineral Density, and Plasma Lipids in Postmenopausal Women: A Randomized Controlled Trial, JAMA 292, 65–74.PubMedCrossRefGoogle Scholar
  16. 16.
    Clarkson, T.B., Anthony, M.S., and Morgan, T.M. (2001) Inhibition of Postmenopausal Atherosclerosis Progression: A Comparison of the Effects of Conjugated Equine Estrogens and Soy Phytoestrogens, J. Clin. Endocrinol. Metab. 86, 41–47.PubMedCrossRefGoogle Scholar
  17. 17.
    Lucas, E.A., Lightfoot, S.A., Hammond, L.J., Devareddy, L., Khalil, D.A., Daggy, B.P., Soung do, Y., and Arjmandi, B.H. (2003) Soy Isoflavones Prevent Ovariectomy-Induced Atherosclerotic Lesions in Golden Syrian Hamster Model of Postmenopausal Hyperlipidemia, Menopause 10, 314–321.PubMedCrossRefGoogle Scholar
  18. 18.
    Kirk, E.A., Sutherland, P., Wang, S.A., Chait, A., and LeBoueuf, R.C. (1998) Dietary Isoflavones Reduce Plasma Cholesterol and Atherosclerosis in C57BL/6 Mice but Not LDL Receptor-Deficient Mice. J. Nutr. 128, 954–959.PubMedGoogle Scholar
  19. 19.
    Adams, M.R., Golden, D.L., Register, T.C., Anthony, M.S., Hodgin, J.B., Maeda, N., and Williams, J.K. (2002) The Atheroprotective Effect of Dietary Soy Isoflavones in Apolipoprotein E-/- Mice Requires the Presence of Estrogen Receptor-Alpha, Arterioscler. Thromb. Vasc. Biol. 22, 1859–1864.PubMedCrossRefGoogle Scholar
  20. 20.
    Yamakoshi, J., Piskula, M.K., Izumi, T., Tobe, K., Saito, M., Kataoka, S., Obata, A., and Kikuchi, M. (2000) Isoflavone Aglycone-Rich Extract Without Soy Protein Attenuates Atherosclerosis Development in Cholesterol-Fed Rabbits, J. Nutr. 130, 1887–1893.PubMedGoogle Scholar
  21. 21.
    Adams, M.R., Golden, D.L., Franke, A.A., Potter, S.M., Smith, H.S., and Anthony, M.S. (2004) Dietary Soy Beta-Conglycinin (7S Globulin) Inhibits Atherosclerosis in Mice. J. Nutr. 134, 511–516.PubMedGoogle Scholar
  22. 22.
    Mortensen, A., Pilegaard, K., Frandsen, H., and Breinholt, V. (2004) Effect of a Soy Supplement on Spontaneous Atherosclerosis in Low Density Lipoprotein Receptor Knockout (LDLR-/-) Mice, Asia Pac. J. Clin. Nutr. 13 (Suppl.), S102 (abs).Google Scholar
  23. 23.
    Wagner, J.D., Schwenke, D.C., Greaves, K.A., Zhang, L., Anthony, M.S., Blair, R.M., Shadoan, M.K., and Willianms, J.K. (2003) Soy Protein with Isoflavones, but Not Isoflavone-Rich Supplement, Improves Arterial Low-Density Lipoprotein Metabolism and Atherogenesis. Arterioscler. Thromb. Vasc. Biol. 23, 2241–2246.PubMedCrossRefGoogle Scholar
  24. 24.
    Adams, M.R., Golden, D.L., Anthony, M.S., Register, T.C., and Williams J.K. (2002) The Inhibitory Effect of Soy Protein Isolate on Atherosclerosis in Mice Does Not Require the Presence of LDL Receptors or Alteration of Plasma Lipoproteins. J. Nutr. 132, 43–49.PubMedGoogle Scholar
  25. 25.
    Alexandersen, P., Haarbo, J., Breinholt, V., and Christiansen, C. (2001) Dietary Phytoestrogens and Estrogen Inhibit Experimental Atherosclerosis, Climacteric. 4, 151–159.PubMedGoogle Scholar
  26. 26.
    Cassidy, A., De Pascual, T.S., and Rimbach, G. (2003) Molecular Mechanisms by Dietary Isoflavones Potentially Prevent Atherosclerosis, Expert Rev. Mol. Med. 5, 1–15.CrossRefPubMedGoogle Scholar
  27. 27.
    Meng, Q.H., Lewis, P., Wahala, K., Adlercreutz, H., and Tikkanen, M. (1992) Incorporation of Esterified Soybean Isoflavones with Antioxidant Activity into Low Density Lipoprotein, Biochim. Biophys. Acta 1438, 369–376.Google Scholar
  28. 28.
    Cazita, P.M., Berti, J.A., Aoki, C., Gidlund, M., Harada, L.M., Nunes, V.S., Quintão, E.C., and Oliveira, H.C. (2003) Cholesteryl Ester Transfer Protein Expression Attenuates Atherosclerosis in Ovariectomized Mice, J. Lipid Res. 44, 33–40.PubMedCrossRefGoogle Scholar
  29. 29.
    Casquero, A.C., Berti, J.A., Salerno, A.G., Bighetti, E.J., Cazita, P.M., Ketelhuth, D.F., Gidlund, M., and Oliveira, H.C. (2006) Atherosclerosis Is Enhanced by Testosterone Deficiency and Attenuated by CETP Expression in Transgenic Mice, J. Lipid Res. 47, 1526–1534.PubMedCrossRefGoogle Scholar
  30. 30.
    Paigen, B., Morrow, A., Holmes, P.A., Mitchell, D., and Willians, R.A. (1987) Quantitative Assessment of Atherosclerotic Lesions Mice, Atherosclerosis 68, 231–240.PubMedCrossRefGoogle Scholar
  31. 31.
    Rubin, E.M., Krauss, R.M., Spangler, E.A., Verstuyft, J.G., and Glift, S.M. (1991) Inhibition of Early Atherogenesis in Transgenic Mice by Human Apolipoprotein AI, Nature 353, 265–267.PubMedCrossRefGoogle Scholar
  32. 32.
    Damasceno, N.R., Goto, H., Rodrigues, F.M., Dias, C.T., Okawabata, F.S., Abdalla, D.S., and Gidlund, M. (2000) Soy Protein Isolate Reduces the Oxidizability of LDL and the Generation of Oxidized LDL Auto Antibodies in Rabbits with Diet-Induced Atherosclerosis, J. Nutr. 130, 2641–2647.PubMedGoogle Scholar
  33. 33.
    Brown, M.S., and Goldstein, J.L. (1983) Lipoprotein Metabolism in the Macrophage: Implications for Cholesterol Deposition in Atherosclerosis, Annu. Rev. Biochem. 52, 223–261.PubMedCrossRefGoogle Scholar
  34. 34.
    Basu, S.K., Goldstein, J.L., Anderson, G.W., and Brown, M.S. (1976) Degradation of Cationized Low Density Lipoprotein and Regulation of Cholesterol Metabolism in Homozygous Familial Hypercholesterolemia Fibroblasts, Proc. Natl. Acad. Sci. USA 73, 3178–3182.PubMedCrossRefGoogle Scholar
  35. 35.
    Dobiasova, M., Stribrna, J., Pritchard, P.H., and Frohlich, J.J. (1992) Cholesterol Esterification Rate in Plasma Depleted of Very Low and Low Density Lipoproteins Is Controlled by the Proportion of HDL2 and HDL3 Subclasses: Study in Hypertensive and Normal Middle-Aged and Septuagenarian Men, J. Lipid Res. 33, 1411–1418.PubMedGoogle Scholar
  36. 36.
    Tsimikas, S., Palinski, W., and Witztum, J.L. (2001) Circulating Autoantibodies to Oxidized LDL Correlate with Arterial Accumulation and Depletion of Oxidized LDL in LDL Receptor-Deficient Mice, Arterioscler. Thromb. Vasc. Biol. 21, 95–100.PubMedGoogle Scholar
  37. 37.
    Ehara, S., Ueda, M., Naruko, T., Haze, K., Itoh, A., Otsuka, M., Komatsu, R., Matsuo, T., Itabe, H., Takano, T., Tsukamoto, Y., Yoshiyama, M., Takeuchi, K., Yoshikawa, J., and Becker, A.E. (2001) Elevated Levels of Oxidized Low Density Lipoprotein Show a Positive Relationship with the Severity of Acute Coronary Syndromes, Circulation 103, 1955–1960.PubMedGoogle Scholar
  38. 38.
    Heikkinen, A.M., Nishkanen, L., Yla-Herttuala, S., Luoma, J., Tuppurainen, M.T., Komulainen, M., and Saarikoski, S. (1998) Postmenopausal Hormone Replacement Therapy and Autoantibodies Against Oxidized LDL, Maturitas 29, 155–161.PubMedCrossRefGoogle Scholar
  39. 39.
    Uint, L., Gebara, O.C.E., Pinto, L.B., Wajngarten, M., Boschov, P., da Luz, P.L., and Gidlund, M. (2003) Hormone Replacement Therapy Increases Levels of Antibodies Against Heat Shock Protein 65 and Certain Species of Oxidized Low Density Lipoprotein, Braz. J. Med. Biol. Res. 36, 491–494.PubMedCrossRefGoogle Scholar
  40. 40.
    Wen, Y., Doyle, M.C.T., Cooke, T., and Feeley, J. (2000) Effect of Menopause on Low-Density Lipoprotein Oxidation: Is Estrogen an Important Determinant? Maturitas 34, 233–238.PubMedCrossRefGoogle Scholar
  41. 41.
    Santanam, N., Sher-Brewer, R., McClatchey, R., Castellano, P.Z., Murphy, A.A., Voelkel, S., and Parthasarathy, S. (1998) Estradiol as an Antioxidant: Incompatible with Its Physiological Concentrations and Function, J. Lipid Res. 39, 2111–2118.PubMedGoogle Scholar
  42. 42.
    Samman, S., Wall, P.M.L., Chan, G.S.M., Smith, S.J., and Petocz, P. (1999) The Effect of Supplementation with Isoflavones on Plasma Lipids and Oxidisability of Low Density Lipoprotein in Premenopausal Women, Atherosclerosis 147, 277–283.PubMedCrossRefGoogle Scholar
  43. 43.
    Barter, P.J., and Kastelein, J.J. (2006) Targeting Cholesteryl Ester Transfer Protein for the Prevention and Management of Cardiovascular Disease, J. Am. Coll. Cardiol. 47(3), 492–499.PubMedCrossRefGoogle Scholar
  44. 44.
    Hodgin, J.B., and Maeda, N. (2002) Estrogen and Mouse Models of Atherosclerosis, Endocrinology 143, 4495–4501.PubMedCrossRefGoogle Scholar
  45. 45.
    Clair, R.S., and Anthony, M. (2005) Soy, Isoflavones and Atherosclerosis. Handb. Exp. Pharmacol. 170, 301–323.PubMedCrossRefGoogle Scholar
  46. 46.
    van der Schouw, Y.T., de Kleijn, M.J., Peeters, P.H., and Grobbee, D.E. (2000) Phyto-oestrogens and Cardiovascular Disease Risk, Nutr. Metab. Cardiovasc. Dis. 10, 154–167.PubMedGoogle Scholar
  47. 47.
    Cassidy, A., and Hooper, L. (2006) Phytoestrogens and Cardiovascular Disease, J. Br. Menopause Soc. 12, 49–56.PubMedCrossRefGoogle Scholar

Copyright information

© AOCS Press 2006

Authors and Affiliations

  • Leiko Asakura
    • 1
  • Patrícia M. Cazita
    • 1
  • Lila M. Harada
    • 1
  • Valéria S. Nunes
    • 1
  • Jairo A. Berti
    • 2
  • Alessandro G. Salerno
    • 2
  • Daniel F. J. Ketelhuth
    • 3
  • Magnus Gidlund
    • 3
  • Helena C. F. Oliveria
    • 2
  • Eder C. R. Quintão
    • 1
  1. 1.Lipids LabUniversity of São Paulo Medical SchoolSão PauloBrazil
  2. 2.Department of Physiology and BiophysicsBiology Institute at State University of Campinas (UNICAMP)São PauloBrazil
  3. 3.Department of ImmunologyBiomedical Sciences Institute at the University of São PauloBrazil

Personalised recommendations