The dietary soy flavonoid genistein abrogates tissue factor induction in endothelial cells induced by the atherogenic oxidized phospholipid oxPAPC
The dietary soy flavonoid genistein abrogates tissue factor induction in endothelial cells induced by the atherogenic oxidized phospholipid oxPAPC
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DOI：
10.1016/j.thromres.2006.07.007
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发表时间：
2007-01-01
影响因子：
7.5
通讯作者：
Kapiotis, Stylianos
中科院分区：
文献类型：
--
作者：
Holzer, Gregor;Esterbauer, Harald;Kapiotis, Stylianos
简介：组织因子（TF）在动脉粥样硬化性血栓形成疾病中凝血酶的产生中起着关键作用。氧化磷脂1-棕榈酰-2-花生四烯酸酰-sn-甘油基-3-磷酸胆碱（ox-PAPC）是最低限度氧化低密度脂蛋白（MM-LDL）的活性化合物，可诱导内皮细胞（EC）产生TF。膳食大豆异黄酮已被声称通过结合雌激素受体、产生一氧化氮（NO）或抑制酪氨酸激酶依赖性途径来逆转导致动脉粥样硬化和相关心血管事件的几个过程。染料木黄酮对活性的影响及其机制，在人脐静脉内皮细胞（HUVEC）和人主动脉内皮细胞（HAEC）中研究oxPAPC诱导的TF的抗原表达和mRNA水平。染料木素废除oxPAPC诱导的TF活性在动脉和静脉的人EC的基础水平，通过功能性凝血测定，并下调oxPAPC诱导的抗原表达通过流式细胞术和mRNA水平定量实时PCR测定。用雌激素受体抑制剂ICI 182，780和NO合酶抑制剂N（ω）-硝基-L-精氨酸甲酯（L-NAME）进行的蛋白质印迹和抑制剂实验表明，该效应可能是通过抑制ERK的磷酸化介导的，但不是上游MEK 1/2。这种作用不是由染料木黄酮的酪氨酸激酶抑制剂活性介导的，因为另一种酪氨酸激酶抑制剂（tyrphostin 25）没有作用。染料木黄酮对TF的作用不涉及与雌激素受体的结合或NO的产生。总之，金雀异黄素降低oxPAPC诱导的TF表达，从而降低EC的血栓前表型，进一步证实和解释膳食金雀异黄素在预防动脉粥样硬化和相关心血管事件中的有益作用。(c)2006爱思唯尔有限公司保留所有权利。
Introduction: Tissue factor (TF) plays a pivotal role in the generation of thrombin in atherothrombotic disease. The oxidized phospholipid 1-palmitoyl-2-arachidonoyi-sn-glycero-3-phosphorylcholine (oxPAPC), an active compound of minimally oxidized tow-density lipoprotein (MM-LDL), induces TF in endothelial cells (EC). The dietary soybean isoflavonoid genistein has been claimed to reverse several processes Leading to atherosclerosis and related cardiovascular events via binding to estrogen receptors, generating nitric oxide (NO) or inhibiting tyrosine kinase-dependent pathways.Methods and materials: The effects and mechanisms of genistein on activity, antigen expression and mRNA levels of oxPAPC-induced TF were studied in human umbilical vein endothelial cells (HUVEC) and human aortic endothetial cells (HAEC).Results and conclusions: Genistein abrogated oxPAPC-induced TF activity in arterial and venous human EC to basal levels, as measured by functional clotting assay, and downregulated oxPAPC-induced antigen expression measured by flow cytometry and mRNA levels quantified by real-time PCR. Western blotting and inhibitor experiments with the estrogen-receptor inhibitor ICI 182,780 and the NO-synthase inhibitor N (omega)-nitro-L-arginine methyl ester (L-NAME) showed that the effect may be mediated via inhibition of phosphorylation of ERK, but not upstream MEK1/2. The effect is not mediated by the tyrosine kinase inhibitor activity of genistein, as another tyrosine kinase inhibitor (tyrphostin 25) had no effect. Binding to the estrogen receptor or generation of NO are not involved in the action of genistein on TF. In conclusion genistein reduces oxPAPC-induced TF expression and thereby the prothrombotic phenotype of EC, further substantiating and explaining the beneficial effects of dietary genistein in preventing atherosclerosis and related cardiovascular events. (c) 2006 Elsevier Ltd. All rights reserved.