Inhibition by soya isoflavones of human polymorphonuclear leukocyte function: possible relevance for the beneficial effects of soya intake.

Lower CVD incidence is reported in Asian populations consuming soya-containing food. As polymorphonuclear leukocytes (PMN) are involved in the risk of CVD, we investigated the modulatory effect of soya isoflavones on several PMN functions and their molecular mechanisms in vitro. PMN, isolated from blood from healthy subjects, were tested upon activation with 1 microm- n-formyl-methyl-leucyl-phenylalanine (fMLP) for superoxide anion production (ferric cytochrome c reduction) and released elastase (chromogenic test). PMN homotypic aggregates stimulated by fMLP or P-selectin in dynamic conditions were detected by optical microscopy. PMN, mixed with thrombin-activated, washed platelets, formed cell aggregates, measured by flow cytometry. Phosphorylation of Pyk2, a focal adhesion kinase, was studied by immunoprecipitation and immunoblotting with specific antibodies. Genistein, daidzein and equol inhibited superoxide anion production (IC50 0.25 (sem 0.1), 21.0 (sem 4.2) and 13.0 (sem 2.8) microm, respectively); the release of elastase was prevented by genistein (IC50 63 (sem 17) microm). PMN homotypic aggregates, stimulated by fMLP, were significantly reduced (24 (sem 12) and 51 (sem 14) % of control) by 100 microm genistein and equol. P-selectin-induced aggregates were reduced to 19 (sem 6), 44 (sem 10) and 28 (sem 9) % of control by 100 microm genistein, daidzein and equol, respectively. Genistein, daidzein and equol also significantly reduced mixed platelet-PMN aggregates (IC50 4.0 (sem 0.9), 57 (sem 6) and 66 (sem 23) microm, respectively). In PMN challenged by fMLP or P-selectin, activation of Pyk2 was prevented by isoflavones. The cardioprotective effect of soya-containing food might be linked to reduction of PMN activation and PMN-platelet interaction, novel targets for the biological effects of soya isoflavones.

Platelet glycoprotein IIb/IIIa polymorphism and coronary artery disease: implications for clinical practice.

Membrane glycoprotein (GP) IIb/IIIa plays a major role in platelet function; indeed it enables stimulated platelets to bind fibrinogen and related adhesive proteins, a process that is considered key in the development of thrombosis. The gene encoding GPIIIa (ITGB3, also known as GP3A) shows a common platelet antigen polymorphism [PL(A1)/PL(A2); expressed by alleles ITGB3*001 and ITGB3*002] that was variably associated with vascular disease. In 1996, the presence of the PL(A2) allele (ITGB3*001) was first reported to increase the risk of coronary heart disease. Shortly after, the interest in this study was increased by the publication of a case report on the death from myocardial infarction of an Olympic athlete who was found to be homozygous for the PL(A2) allele. Overviews of the published studies on the PL(A1)/PL(A2) polymorphism and coronary risk suggest an influence of the PL(A2) allele on the clinical phenotype and the interaction with other environmental factors. In particular, the strongest effect of the ITGB3 PL(A2) allele was expressed on the risk of occlusion after revascularization procedures, mainly after stent implantation, a condition in which platelet activation is more important as compared with other stenotic mechanisms. In the future, the identification of patients who are particularly responsive to GPIIb/IIIa antagonist therapy (e.g. those with the PL(A2) allele) might help to improve the treatment efficacy in this relatively small population. In a mechanism possibly unrelated to its effect on platelet reactivity to aggregating stimuli, the presence of the PL(A2) allele might influence the antiaggregatory effect of platelet inhibitory drugs such as aspirin (acetylsalicylic acid), clopidogrel, and GPIIb/IIIa antagonists. Although interesting, current data does not yet have direct clinical implications for patient risk identification and drug therapy tailoring. Larger studies are necessary to define the role of the PL(A2) allele in more homogeneous groups where platelet GPIIb/IIIa activation might be particularly relevant.