Ginsenoside Rb1 Decreases Injury-Induced Vascular Restenosis

人参皂苷 Rb1 减少损伤引起的血管再狭窄

基本信息

批准号：
7943144
负责人：
Wei Zhou
金额：
$ 14.18万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943144
关键词：
Aging Angioplasty Animal Model Apolipoprotein E Arterial Fatty Streak Atherosclerosis Balloon Angioplasty Blood Vessels Cardiovascular Diseases Cardiovascular system Carotid Artery Injuries Cell Proliferation Cellular Stress Clinical Clinical Research Common carotid artery Complementary and alternative medicine Coronary artery Development Elderly Endothelial Cells Endothelium Family suidae Foundations Free Radicals Functional disorder Ginseng Preparation Ginsenosides Histology Homocysteine Homocystine Human Hyperplasia Imaging Techniques Injury Intervention Investigation Lead Life Style Mediating Methods Modeling Molecular Monitor Morbidity - disease rate Mus Oxidative Stress Patients Peripheral Vascular Diseases Plant Roots Plasma Play Population Procedures Production Reactive Oxygen Species Recording of previous events Regulation Risk Risk Factors Role Signal Pathway Smooth Muscle Myocytes Solid Source Superoxides System Systems Analysis Therapeutic Vasomotor aging population alternative treatment atherogenesis ginsenoside Rb1 immunoreactivity in vivo injured interdisciplinary approach migration molecular imaging mortality novel strategies protective effect public health relevance research study restenosis treatment strategy

项目摘要

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.

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，临床证据增加了心血管疾病的潜在益处。研究表明，人参的活性成分，在动脉粥样硬化斑块形成和各种血管损伤中具有保护作用。我们假设人参根和人参皂苷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。我们最近已经证明了Ginsenoside RB1（RB1）阻止了同型半胱氨酸（HCY）诱导的对内皮血管舒张肌功能，自由基生产和eNOS表达的有害影响。为了扩展初步研究，我们提出了一项更全面的研究，以阐明RB1对血管损伤后HCYMEGGEMSTARGATED细胞应激的分子机制，细胞效应和体内影响。我们的中心假设是，RB1通过维持功能性eNOS系统并减少氧化应激，有效地阻止了HCY增强的血管功能障碍和再狭窄。提出了两个具体目的：具体目标1：确定HCY诱导的细胞应激中RB1中的ENOS救援和ROS抑制的分子机制。假设：eNOS功能障碍和氧化应激在HCY诱导的动脉粥样硬化和再狭窄中都起着重要作用。这两个系统是密切相关但不同的实体。 RB1通过调节eNOS表达和O2.-生产来发挥其保护作用。在此目标中，我们将通过分析人类冠状动脉内皮细胞（HCAECS）中的eNOS表达，活性和调节来研究eNOS系统（特定AIM 1A）。我们还将研究HCAEC中的活性氧（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（特定目标1B）。具体目标2：确定RB1对指认识线损伤的鼠模型中HCY-augment的内膜增生的影响。将使用载脂蛋白E缺乏（APOE - / - ）小鼠引起的导丝引导引起的颈动脉损伤模型。再狭窄的程度和组成将使用分子成像技术和组织学方法来监测。该应用可能有可能导致一种新的策略，即融合了互补和替代药物，以改善与HCY相关的细胞应激和血管成形术后内膜增生。鉴于它们的治疗应用史以及对其分子作用的最新发现，人参化合物的开发是一个很好的机会。我们的应用程序利用一种多学科的方法来探索RB1的机制和体内效应。我们希望该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的治疗策略。公共卫生相关性：该应用程序利用一种全面的分子，细胞和动物模型方法来研究人参皂苷RB1对同型半胱氨酸外生半胱氨酸的血管功能障碍的作用和机制。该应用可能会导致一种新的策略，即融合了互补和替代药物以改善风险因素相关的细胞应激。我们希望我们的调查能为大规模临床研究建立坚实的基础，并为老龄化人群的血管再狭窄提供另一种治疗策略。