Anti-atherogenic effects of soy-isoflavones

大豆异黄酮的抗动脉粥样硬化作用

基本信息

批准号：
6447520
负责人：
RAKESH P. PATEL
金额：
$ 7.18万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2003-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant) The association of a healthy diet and prevention of chronic inflammatory diseases has long been recognized. An important example are the soy- isoflavones, consumption of which is associated with a decrease in the incidence of atherosclerosis. Central to the beneficial effects of these compounds are their interactions with reactive oxygen (ROS) and nitrogen species (RNS) that are generated both endogenously and via environmental exposure. Little is known, however, on the biological effects of the products of these reactions. It is proposed herein that derivatives of isoflavones, obtained after reaction with inflammatory oxidants, have potent anti- atherogenic effects. Oxidative modification of low-density lipoprotein (LDL) and subsequent effects on vascular cell function are key elements of atherogenesis. Inhibition of LDL oxidation and modulation of cell signaling pathways have been proposed as key anti-atherogenic mechanisms for the isoflavones. In this proposal, these concepts are extended and the potential anti-atherogenic roles of novel derivatives of isoflavones formed at sites of inflammation (namely chlorinated and nitrated isoflavones) explored. This is important since isoflavones in their native form are poor inhibitors of LDL oxidation in vitro, yet their consumption is associated with a decrease in lipid peroxidation. Furthermore, the effects of isoflavones on key inflammatory signaling pathways involved in atherogenesis are poorly defined and in some instances pro-inflammatory effects demonstrated. Specifically, native isoflavones have been shown to stimulate monocyte-endothelial cell interactions, an early event in lesion formation. Based on the concepts discussed above and preliminary data presented herein, the investigators hypothesize that the anti-atherogenic effects of soy-isoflavones are mediated by products derived from their reactions with ROS and RNS. This hypothesis will be pursued by testing the specific aims to determine the effect of native and modified isoflavones on: (1) LDL oxidation, (2) oxLDL and ROS/RNS-induced cell death in vascular endothelial cells, and (3) oxLDL-dependent monocyte firm adhesion to endothelial cells. These studies will yield novel insights into the interplay between isoflavones and ROS/RNS that impact on both direct anti-oxidant properties, and more subtle effects on inflammatory cell signaling pathways. Also, it is anticipated that mechanistic insights gained will provide information on possible herapeutic development of isoflavones and other polyphenols.

描述（由申请人提供）健康饮食与预防慢性炎症的关系疾病早已被人们所认识。一个重要的例子是大豆—— 异黄酮，其消耗量与减少动脉粥样硬化的发生率。这些有益效果的核心化合物与活性氧 (ROS) 和氮的相互作用内源性和环境性产生的物种（RNS）接触。然而，人们对产品的生物效应知之甚少这些反应。本文提出异黄酮衍生物，与炎症氧化剂反应后获得，具有有效的抗炎作用致动脉粥样硬化效应。低密度脂蛋白（LDL）的氧化修饰以及随后对血管细胞功能的影响是动脉粥样硬化。抑制 LDL 氧化和调节细胞信号传导途径已被提议作为关键的抗动脉粥样硬化机制异黄酮。在本提案中，这些概念得到了扩展，并且潜在的在部位形成的新型异黄酮衍生物的抗动脉粥样硬化作用探索了炎症（即氯化和硝化异黄酮）。这是很重要，因为天然形式的异黄酮是低密度脂蛋白的不良抑制剂体外氧化，但它们的消耗与脂质过氧化。此外，异黄酮对关键的影响参与动脉粥样硬化形成的炎症信号通路尚不清楚在某些情况下，显示出促炎作用。具体来说，天然异黄酮已被证明可以刺激单核细胞内皮细胞相互作用，病变形成的早期事件。基于概念如上所述和本文提供的初步数据，研究人员假设大豆异黄酮的抗动脉粥样硬化作用是介导的与 ROS 和 RNS 反应产生的副产物。这个假设将通过测试具体目标来确定原生的效果和修饰异黄酮对：(1) LDL 氧化，(2) oxLDL 和 ROS/RNS 诱导血管内皮细胞的细胞死亡，以及 (3) oxLDL 依赖性单核细胞与内皮细胞牢固粘附。这些研究将产生新的见解异黄酮和 ROS/RNS 之间的相互作用对两者都有直接影响抗氧化特性，并对炎症细胞产生更微妙的影响信号通路。此外，预计还会获得机械见解将提供有关异黄酮可能的治疗开发的信息和其他多酚。