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

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，在动物模型和人体中进行的各种研究评估了体内铁含量增加对动脉粥样硬化的影响，但得出的结果并不一致。在过去的十年里，我们对铁生物学的理解经历了一次彻底的修正，对这一主题的许多研究的设计和解释提出了问题。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。在最近的一项NIH倡议（PA-09-244）中，研究重点是心血管疾病和营养领域，其益处或风险的证据尚不确定，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，它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，与其他炎症性疾病一样，全身和局部炎症会增加铁调节肽激素hepcidin的产生。Hepcidin通过抑制巨噬细胞释放铁来发挥作用，并且对摄取红细胞和凋亡/坏死细胞的巨噬细胞的动脉粥样硬化斑块具有相同的作用。hepcidin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）hepcidin产生的影响2。在apoE-/-背景下，确定巨噬细胞铁增加对熨熨铁小鼠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铁在动脉粥样硬化中作用的重要问题。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来帮助降低与心血管疾病相关的发病率和死亡率。

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.