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

• 批准号: 8028193
• 负责人: Elizabeta Nemeth
• 金额: $ 26.95万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/8028193
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the leading cause of death in developed countries. Understanding the risk factors for this disease is a high priority. Building on recent advances in the field of iron metabolism, we propose to test how iron accumulation in atherosclerotic plaques promotes cardiovascular disease.

描述（由申请人提供）：铁在促进动脉粥样硬化中的可能作用是一个尚未解决的主要问题。在过去的30年里，在动物模型和人类中进行的各种研究评估了体内铁增加对动脉粥样硬化的影响，但结果不一致。在过去的十年中，我们对铁生物学的理解经历了一次彻底的修订，对该主题的众多研究的设计和解释提出了质疑。我们将利用对铁稳态的新认识来探讨铁在动脉粥样硬化中的作用。如最近NIH倡议（PA-09-244）所示，关注心血管疾病和营养领域的研究（获益或风险证据不确定）已被确定为高度优先事项。我们建议测试以下概念框架。铁，被认为是产生活性氧的有效催化剂，可能通过增加斑块中的氧化应激，氧化积累的脂质和促进炎症来加速动脉粥样硬化。在动脉粥样硬化中，与其他炎性疾病一样，全身和局部炎症增加了铁调节肽激素铁调素的产生。铁调素通过抑制铁从巨噬细胞的释放发挥作用，并且在摄取红细胞和凋亡/坏死细胞的巨噬细胞上的动脉粥样硬化斑块中具有相同的作用。铁调素介导的铁在斑块巨噬细胞中的积累和由此产生的炎症构成了一个自我放大的过程，是动脉粥样硬化的重要促进因素。我们的具体目标是：1.确定动脉粥样硬化对apoE-/-小鼠全身（肝脏）和局部（斑块巨噬细胞）铁调素产生的影响2。在apoE-/-背景的flatiron小鼠中确定增加的巨噬细胞铁对动脉粥样硬化进展的影响这项研究的成功完成将有助于解决关于铁在动脉粥样硬化中的作用的重要问题。与其他可改变的风险因素类似，可以设计减少斑块铁的策略，以帮助降低与心血管疾病相关的发病率和死亡率。 公共卫生相关性：动脉粥样硬化是发达国家的主要死亡原因。了解这种疾病的风险因素是一个高度优先事项。基于铁代谢领域的最新进展，我们建议测试动脉粥样硬化斑块中的铁积累如何促进心血管疾病。