Ginsenoside Rb1 Decreases Injury-Induced Vascular Restenosis

描述（由申请人提供）：人参根是最广泛认可的草药补充剂之一，临床证据表明其对心血管疾病具有潜在益处。研究表明，人参皂苷是人参的活性成分，对动脉粥样硬化斑块的形成和各种血管损伤具有保护作用。我们推测人参根和黄芪对血管成形术引起的血管损伤和血管成形术后再狭窄具有保护作用。我们最近已经证明，Rb 1（Rb 1）块同型半胱氨酸（HCY）诱导的内皮血管功能，自由基的产生和eNOS表达的不利影响。为了扩展初步研究，我们提出了一个更全面的调查，以阐明分子机制，细胞的影响，并在体内的影响，Rb 1对HCY夸大细胞应力血管损伤后。我们的中心假设是Rb 1通过维持功能性eNOS系统和降低氧化应激有效地阻断HCY增强的血管功能障碍和再狭窄。提出了两个具体目标：具体目标1：确定在HCY诱导的细胞应激中Rb 1介导的eNOS拯救和ROS抑制的分子机制。假说：内皮型一氧化氮合酶功能障碍和氧化应激在同型半胱氨酸诱导的动脉粥样硬化和再狭窄中起重要作用。这两个系统密切相关，但不同的实体。Rb 1通过调节eNOS表达和O2.-生产在这个目标中，我们将通过分析eNOS在人冠状动脉内皮细胞（HCAECs）中的表达、活性和调节来研究eNOS系统（具体目标1a）。我们还将研究HCAEC中活性氧（ROS）产生的来源，并确定ROS介导的信号通路是否参与HCY诱导的内皮功能障碍（特定目的1b）。具体目的2：确定Rb 1对导丝损伤后小鼠模型中HCY增强的内膜增生的影响。将在载脂蛋白E缺陷（ApoE-/-）小鼠中使用导丝诱导的颈总动脉损伤模型。将使用分子成像技术和组织学方法监测再狭窄的程度和组成。这种应用可能会导致一种新的策略，将补充和替代药物，以改善同型半胱氨酸相关的细胞应激和血管成形术后内膜增生。人参化合物的开发是一个很好的机会，因为它们的治疗应用历史和最近发现的分子作用。我们的应用程序利用多学科的方法来探索Rb 1的机制和体内效应。我们希望这一应用将为大规模临床研究建立坚实的基础，并有可能为血管损伤和再狭窄提供替代治疗策略。 公共卫生相关性：本申请利用全面的分子、细胞和动物模型方法来研究抗Rb 1对同型半胱氨酸夸大的血管功能障碍的影响和机制。这种应用可能会导致一种新的策略，将补充和替代药物，以改善风险因素相关的细胞压力。我们希望我们的研究将为大规模的临床研究奠定坚实的基础，并为老年人群中的血管再狭窄提供替代治疗策略。

DESCRIPTION (provided by applicant): Ginseng root is one of the most widely recognized herbal supplements with increased clinical evidence of potential benefits in cardiovascular diseases. Studies have shown that ginsenosides, active constituents of ginseng, have protective roles in atherosclerotic plaque formation and various vascular injuries. We hypothesize that ginseng root and ginsenoside have protective effects against angioplasty-induced vascular damage and post-angioplasty restenosis. We recently have demonstrated that ginsenoside Rb1 (Rb1) blocks homocysteine (HCY)-induced detrimental effects on endothelial vasomotor function, free-radical production, and eNOS expression. To extend the preliminary studies, we propose a more comprehensive investigation to elucidate the molecular mechanisms, cellular effects, and in vivo influences of Rb1 on HCY- exaggerated cellular stress following vascular injury. Our central hypothesis is that Rb1 effectively blocks HCY-augmented vascular dysfunction and restenosis by maintaining a functional eNOS system and decreasing oxidative stress. Two specific aims are proposed: Specific Aim 1: Determine the molecular mechanisms of Rb1-medicated eNOS rescue and ROS suppression in HCY-induced cellular stress. Hypothesis: both eNOS dysfunction and oxidative stress play important roles in HCY-induced atherogenesis and restenosis. These two systems are intimately related, yet distinct entities. Rb1 exerts its protective effects by modulating eNOS expression and O2.- production. In this aim, we will study the eNOS system by analyzing eNOS expression, activity, and regulation in human coronary artery endothelial cells (HCAECs) (Specific Aim 1a). We will also investigate the sources of reactive oxygen species (ROS) production in HCAECs and determine whether ROS-mediated signaling pathway is involved in HCY-induced endothelial dysfunction (Specific Aims 1b). Specific Aim 2: Determine the effects of Rb1 on HCY-augmented intimal hyperplasia in a post-guide wire injured murine model. A guidewire-induced common carotid artery injury model in Apolipoprotein E deficient (ApoE-/-) mice will be used. Degree and composition of restenosis will be monitored using a molecular imaging techniques and histology methods. This application may potentially lead to a new strategy of incorporating complementary and alternative medicine to ameliorate HCY-associated cellular stress and post-angioplasty intimal hyperplasia. Development of ginseng compounds is a great opportunity given their history of therapeutic applications and recent discoveries of their molecular actions. Our application utilizes a multidisciplinary approach to explore the mechanisms and in vivo effects of Rb1. We hope that this application will establish a solid foundation for large- scale clinical research and potentially provide an alternative treatment strategy for vascular damages and restenosis. PUBLIC HEALTH RELEVANCE: This application utilizes a comprehensive molecular, cellular, and animal model approach to investigate the effects and mechanisms of ginsenoside Rb1 on homocysteine-exaggerated vascular dysfunction. This application may potentially lead to a new strategy of incorporating complementary and alternative medicine to ameliorate risk factor-associated cellular stress. We hope that our investigation will establish a solid foundation for large-scale clinical research and provide an alternative treatment strategy for vascular restenosis in an aging population.