Soy-isoflavone-enriched foods and inflammatory biomarkers of cardiovascular disease risk in postmenopausal women: interactions with genotype and equol production.

BACKGROUND Dietary isoflavones are thought to be cardioprotective because of their structural similarity to estrogen. The reduction of concentrations of circulating inflammatory markers by estrogen may be one of the mechanisms by which premenopausal women are protected against cardiovascular disease. OBJECTIVE Our aim was to investigate the effects of isolated soy isoflavones on inflammatory biomarkers [von Willebrand factor, intracellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), E-selectin, monocyte chemoattractant protein 1, C-reactive protein (CRP), and endothelin 1 concentrations]. Differences with respect to single-nucleotide polymorphisms in selected genes [estrogen receptor alpha (XbaI and PvuII), estrogen receptor beta [ERbeta (AluI) and ERbeta[cx] (Tsp509I), endothelial nitric oxide synthase (Glu298Asp), apolipoprotein E (Apo E2, E3, and E4), and cholesteryl ester transfer protein (TaqIB)] and equol production were investigated. DESIGN One hundred seventeen healthy European postmenopausal women participated in this randomized, double-blind, placebo-controlled, crossover dietary intervention trial. Isoflavone-enriched (genistein-to-daidzein ratio of 2:1; 50 mg/d) or placebo cereal bars were consumed for 8 wk, with a washout period of 8 wk between the crossover. Plasma inflammatory factors were measured at 0 and 8 wk of each study arm. RESULTS Isoflavones improved CRP concentrations [odds ratio (95% CI) for CRP values >1 mg/L for isoflavone compared with placebo: 0.43 (0.27, 0.69)]; no significant effects of isoflavone treatment on other plasma inflammatory markers were observed. No significant differences in the response to isoflavones were observed according to subgroups of equol production. Differences in the VCAM-1 response to isoflavones and to placebo were found with ERbeta AluI genotypes. CONCLUSION Isoflavones have beneficial effects on CRP concentrations, but not on other inflammatory biomarkers of cardiovascular disease risk in postmenopausal women, and may improve VCAM-1 in an ERbeta gene polymorphic subgroup.

[1]  A. Lerman,et al.  Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. , 1991, The New England journal of medicine.

[2]  B. Binder,et al.  Polar secretion of endothelin-1 by cultured endothelial cells. , 1992, The Journal of biological chemistry.

[3]  W D Dupont,et al.  Analysis of the PvuII restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. , 1992, Cancer research.

[4]  A. Blann Is raised von Willebrand factor a marker of endothelial cell damage? , 1993, Medical hypotheses.

[5]  A. Quyyumi,et al.  Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. , 1994, Circulation.

[6]  R. T. Lie,et al.  Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. , 1994, Circulation.

[7]  P. Ganz,et al.  Estrogen Improves Endothelium-Dependent, Flow-Mediated Vasodilation in Postmenopausal Women , 1994, Annals of Internal Medicine.

[8]  J. J. Smith,et al.  Estrogen inhibits the response-to-injury in a mouse carotid artery model. , 1995, The Journal of clinical investigation.

[9]  R. Cannon,et al.  Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. , 1997, The American journal of cardiology.

[10]  E. Boerwinkle,et al.  Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. , 1997, Circulation.

[11]  J. Isner,et al.  Estradiol accelerates functional endothelial recovery after arterial injury. , 1997, Circulation.

[12]  F. Stanczyk,et al.  Endothelin levels decrease after oral and nonoral estrogen in postmenopausal women with increased cardiovascular risk factors. , 1997, Fertility and sterility.

[13]  J. Hebebrand,et al.  Systematic mutation screening of the estrogen receptor beta gene in probands of different weight extremes: identification of several genetic variants. , 1998, The Journal of clinical endocrinology and metabolism.

[14]  H. Itoh,et al.  Endothelial nitric oxide synthase gene is positively associated with essential hypertension. , 1998, Hypertension.

[15]  E. Barrett-Connor,et al.  Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. , 1999, Circulation.

[16]  P. Ridker,et al.  C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. , 2000, The New England journal of medicine.

[17]  H. Adlercreutz,et al.  Interindividual Variation in Metabolism of Soy Isoflavones and Lignans: Influence of Habitual Diet on Equol Production by the Gut Microflora , 2000, Nutrition and cancer.

[18]  D. Corella,et al.  Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with plasma lipid levels in a healthy Spanish population. , 2000, Atherosclerosis.

[19]  W. Haskell,et al.  The effect of soy protein with or without isoflavones relative to milk protein on plasma lipids in hypercholesterolemic postmenopausal women. , 2001, The American journal of clinical nutrition.

[20]  P. Ganz,et al.  Role of Endothelin-1 in the Active Constriction of Human Atherosclerotic Coronary Arteries , 2001, Circulation.

[21]  K. Hermansen,et al.  Beneficial effects of a soy-based dietary supplement on lipid levels and cardiovascular risk markers in type 2 diabetic subjects. , 2000, Diabetes care.

[22]  Heidi D Nelson,et al.  Postmenopausal hormone replacement therapy: scientific review. , 2002, JAMA.

[23]  W. Sutherland,et al.  Effect of hormone replacement therapy on inflammation‐sensitive proteins in post‐menopausal women with Type 2 diabetes , 2002, Diabetic medicine : a journal of the British Diabetic Association.

[24]  D. Altavilla,et al.  The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women. , 2002, Atherosclerosis.

[25]  K. Setchell,et al.  The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. , 2002, The Journal of nutrition.

[26]  E. Bleecker,et al.  Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. , 2002, The New England journal of medicine.

[27]  E. Bleecker,et al.  Common Estrogen Receptor Polymorphism Augments Effects of Hormone Replacement Therapy on E-Selectin but Not C-Reactive Protein , 2002, Circulation.

[28]  O. Ylikorkala,et al.  Evidence of a lack of effect of a phytoestrogen regimen on the levels of C-reactive protein, E-selectin, and nitrate in postmenopausal women. , 2003, The Journal of clinical endocrinology and metabolism.

[29]  A. Blum,et al.  Effects of oral soy protein on markers of inflammation in postmenopausal women with mild hypercholesterolemia. , 2003, American heart journal.

[30]  A. Minihane,et al.  Gut metabolism and cardioprotective effects of dietary isoflavones , 2003 .

[31]  D. Cucinotta,et al.  Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study. , 2003, The American journal of medicine.

[32]  A. Minihane,et al.  Effect of genistein and daidzein on platelet aggregation and monocyte and endothelial function. , 2003, The British journal of nutrition.

[33]  A. Villablanca,et al.  Soy protein with isoflavones has favorable effects on endothelial function that are independent of lipid and antioxidant effects in healthy postmenopausal women. , 2003, The American journal of clinical nutrition.

[34]  S. Reddy,et al.  17-Epiestriol, an Estrogen Metabolite, Is More Potent Than Estradiol in Inhibiting Vascular Cell Adhesion Molecule 1 (VCAM-1) mRNA Expression* , 2003, The Journal of Biological Chemistry.

[35]  P. Nestel,et al.  Isoflavones Reduce Arterial Stiffness: A Placebo-Controlled Study in Men and Postmenopausal Women , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[36]  Jian‐Jun Li,et al.  C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases. , 2004, Medical hypotheses.

[37]  A. Minihane,et al.  Sulfation of genistein alters its antioxidant properties and its effect on platelet aggregation and monocyte and endothelial function. , 2004, Biochimica et biophysica acta.

[38]  M. Mori,et al.  Suppression by 17beta-estradiol of monocyte adhesion to vascular endothelial cells is mediated by estrogen receptors. , 2004, Life sciences.

[39]  K. Dahlman-Wright,et al.  Association of estrogen receptor β gene polymorphisms with bulimic disease in women , 2004, Molecular Psychiatry.

[40]  S. Devaraj,et al.  Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role , 2005, Current opinion in nephrology and hypertension.

[41]  D. Grobbee,et al.  Randomized controlled trial of the effects of soy protein containing isoflavones on vascular function in postmenopausal women. , 2005, The American journal of clinical nutrition.

[42]  J. Hallund,et al.  Absorption of isoflavones in humans: effects of food matrix and processing. , 2006, The Journal of nutritional biochemistry.