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。中国的各种研究 在过去的30年里，动物模型和人类评估了体内铁含量增加对 动脉粥样硬化，但结果不一致。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改，对许多关于 主题。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。 研究集中在心血管疾病和营养领域，但没有确凿证据证明有益 或风险已被确定为高度优先事项，如美国国立卫生研究院最近的一项倡议(PA-09-244)所示。 我们建议测试以下概念框架。铁，被认为是一种产生 活性氧物种，可能通过增加斑块中的氧化应激来加速动脉粥样硬化， 氧化积聚的脂肪，促进炎症。在动脉粥样硬化中，如在其他炎症性疾病中 疾病、全身和局部炎症会增加铁调节多肽激素的产生 海普西丁。海普西丁通过抑制巨噬细胞释放铁来发挥作用，并将具有相同的 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。这个 海普西丁介导的铁在斑块巨噬细胞中的积聚和由此引起的炎症构成了 自我放大过程，是动脉粥样硬化的重要促进剂。 我们的具体目标是： 1.明确动脉粥样硬化对全身(肝脏)和局部(斑块巨噬细胞)的影响 ApoE-/-小鼠产生海普西丁的研究 2.明确巨噬细胞铁增加对Flatiron小鼠动脉粥样硬化进展的影响 关于apoE-/-背景 这项研究的成功完成将有助于解决有关铁在人体内的作用的重要问题 动脉硬化。类似于其他可改变的危险因素，可以设计出减少斑块铁的策略。 以帮助降低与心血管疾病相关的发病率和死亡率。

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.