The role of iron in atherosclerosis: application of new iron biology

铁在动脉粥样硬化中的作用：新铁生物学的应用

基本信息

批准号：
8208174
负责人：
Elizabeta Nemeth
金额：
$ 15.4万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208174
关键词：
Acute-Phase Proteins Animal Model Apolipoprotein E Apoptotic Area Arterial Fatty Streak Atherosclerosis Biology Cardiovascular Diseases Cardiovascular system Cause of Death Cells Chronic Data Developed Countries Dietary Iron Disease Endocytosis Erythrocytes Exploratory/Developmental Grant Feedback Foundations Generations Health Heart Diseases Hepatic Hepatocyte Hereditary hemochromatosis Homeostasis Hormones Human Inflammation Inflammatory Inherited Intestines Investigation Iron Lesion Lipids Liver Low Density Lipoprotein oxidation Lung Mediating Morbidity - disease rate Mus Mutation Nature Necrosis Oxidative Stress Physical activity Plasma Process Production Public Health Reactive Oxygen Species Recycling Research Research Personnel Risk Risk Factors Role Systemic disease Testing Tissues United States National Institutes of Health absorption cardiovascular disorder risk catalyst design heart disease risk hepcidin iron metabolism macrophage metal transporting protein 1 modifiable risk mortality mouse model nutrition paracrine peptide hormone promoter receptor

项目摘要

ABSTRACT The possible role of iron in the promotion of atherosclerosis is a major unresolved question. Various studies in animal models and humans over the last 30 years assessed the effect of increased body iron on atherosclerosis but have yielded inconsistent results. In the last decade, our understanding of iron biology underwent a radical revision, raising questions about the design and interpretation of numerous studies on the subject. We will use the new understanding of iron homeostasis to explore the role of iron in atherosclerosis. Research focused on cardiovascular disease and nutrition areas with inconclusive evidence of benefit or risk has been identified as a high priority as indicated in a recent NIH initiative (PA-09-244). We propose to test the following conceptual framework. Iron, known as a potent catalyst for generation of reactive oxygen species, likely accelerates atherosclerosis by increasing oxidative stress in the plaque, oxidizing accumulated lipids and promoting inflammation. In atherosclerosis, as in other inflammatory diseases, systemic and local inflammation increases the production of the iron-regulatory peptide hormone hepcidin. Hepcidin functions by inhibiting the release of iron from macrophages, and would have the same effect in the atherosclerotic plaque on macrophages that ingest erythrocytes and apoptotic/necrotic cells. The hepcidin-mediated accumulation of iron in plaque macrophages and the resulting inflammation constitutes a self-amplifying process and is an important promoter of atherosclerosis. Our specific aims are: 1. Define the effect of atherosclerosis on systemic (hepatic) and local (plaque macrophage) hepcidin production in apoE-/- mice 2. Define the effect of increased macrophage iron on atherosclerosis progression in flatiron mice on apoE-/- background Successful completion of this study will help resolve important questions about the role of iron in atherosclerosis. Similar to other modifiable risk factors, strategies for reduction of plaque iron could be devised to help reduce the morbidity and mortality associated with cardiovascular disease.

抽象的铁在促进动脉粥样硬化中可能发挥的作用是一个尚未解决的重大问题。各种研究动物模型和人类在过去 30 年中评估了体内铁含量增加对健康的影响动脉粥样硬化，但产生了不一致的结果。在过去的十年中，我们对铁生物学的理解进行了彻底的修订，对众多研究的设计和解释提出了质疑主题。我们将利用对铁稳态的新认识来探索铁在动脉粥样硬化中的作用。研究重点是心血管疾病和营养领域，但其益处尚无确凿证据如 NIH 最近的一项倡议 (PA-09-244) 所示，风险已被确定为高度优先事项。我们建议测试以下概念框架。铁，被称为产生的有效催化剂活性氧可能通过增加斑块中的氧化应激来加速动脉粥样硬化，氧化积累的脂质并促进炎症。在动脉粥样硬化中，与其他炎症一样疾病、全身和局部炎症会增加铁调节肽激素的产生铁调素。铁调素通过抑制巨噬细胞释放铁来发挥作用，并且具有相同的作用动脉粥样硬化斑块对吞噬红细胞和凋亡/坏死细胞的巨噬细胞的影响。这铁调素介导的铁在斑块巨噬细胞中的积累以及由此产生的炎症构成了自我放大过程，是动脉粥样硬化的重要促进者。我们的具体目标是： 1. 定义动脉粥样硬化对全身（肝脏）和局部（斑块巨噬细胞）的影响 apoE-/- 小鼠中铁调素的产生 2. 确定增加巨噬细胞铁对熨斗小鼠动脉粥样硬化进展的影响在 apoE-/- 背景上这项研究的成功完成将有助于解决有关铁在体内的作用的重要问题。动脉粥样硬化。与其他可改变的危险因素类似，可以设计减少斑块铁的策略帮助降低与心血管疾病相关的发病率和死亡率。