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

摘要 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。各种研究， 在过去的30年里，动物模型和人类评估了增加体内铁对 动脉粥样硬化，但产生了不一致的结果。在过去的十年里，我们对铁生物学的理解 进行了彻底的修改，引发了对众多研究的设计和解释的质疑 话题吧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。 研究集中在心血管疾病和营养领域，没有确凿的证据表明有益 或风险已被确定为一个高度优先级，在最近的NIH倡议（PA-09-244）。 我们建议测试以下概念框架。铁，被认为是一种有效的催化剂， 活性氧可能通过增加斑块中的氧化应激而加速动脉粥样硬化， 氧化积累的脂质并促进炎症。在动脉粥样硬化中，如在其他炎性 疾病，全身和局部炎症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， 动脉粥样硬化斑块中对吞噬红细胞和凋亡/坏死细胞的巨噬细胞的影响。的 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全身（肝脏）和局部（斑块巨噬细胞）的影响 apoE-/-小鼠中hepcidin产生 2.确定增加的巨噬细胞铁对flatiron小鼠动脉粥样硬化进展的影响 apoE-/-背景 这项研究的成功完成将有助于解决有关铁的作用的重要问题， 动脉粥样硬化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 帮助降低与心血管疾病相关的发病率和死亡率。

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.