Implications of the Cardiac Hepcidin/Ferroportin axis for the Management of Iron Deficiency in Heart Failure

铁是生命所必需的。它不仅是合成血红蛋白所必需的，它在我们的身体中携带氧气，也是我们细胞内产生能量的酶的功能所必需的。事实上，即使在血红蛋白水平正常的情况下，缺铁也会降低运动能力。与此同时，细胞内过多的铁是有毒的，因为它会促进破坏性氧化剂的产生。因此，控制铁的水平对于我们组织的健康功能是必不可少的。组织从血液中获取铁。血液中的铁来自三个不同的来源：从旧血细胞中回收铁的脾，储存铁的肝脏，以及从饮食中吸收铁的肠道。铁通过一种名为铁蛋白的铁输出蛋白从这些器官输出到血液中。当血液中的铁含量过高时，肝脏会产生一种名为海普西丁的荷尔蒙，它会阻止铁蛋白，从而使血液中的铁含量恢复正常。炎症也会刺激海普西丁的产生。正因为如此，许多患有炎症的患者，如心脏病和肾脏疾病，他们的血液中含有太多的海普西丁。这会抑制肠道对铁的吸收，并导致铁被锁在肝脏和脾内。这就是为什么许多慢性病患者血液中铁含量较低，被描述为“缺铁”的原因。近年来，对这些患者的研究表明，这种缺铁会加剧心力衰竭，增加死亡率。现在有很多针对寻找治疗这种缺铁症的最佳方法的努力。给这些患者口服铁不起作用，因为肠道中的铁吸收被海普西丁阻断。一种将铁直接注入血液(通过静脉途径)的新疗法已经开发并推出，用于治疗心脏病患者的铁缺乏。在过去的五年里，我在实验室的工作发现，心脏细胞使用铁蛋白来控制它们内部的铁量。当我们制造出只在心脏中缺乏铁蛋白，但在肠道、脾和肝脏中有完整的铁蛋白的小鼠时，这些小鼠患上了致命的心力衰竭，因为心脏细胞中保留了太多的铁。就像其他部位的铁蛋白一样，心脏中的铁蛋白也可以被海普西丁阻断。基于这一发现，我们假设患者体内高水平的海普西丁也会阻断心脏细胞中的铁蛋白，导致铁保留在心脏中。当血液中铁的可获得性较低时，这种铁滞留可以保护心脏免受缺铁的影响。然而，当血液中铁的利用率很高时，特别是在静脉输铁后，这种滞留可能会导致心脏中有毒的铁积累。这项研究的目的是检验这一假设。我们将使用心力衰竭的小鼠模型和人类样本来完成这项工作。这项研究将由我的团队在牛津大学与研究和治疗心力衰竭患者铁缺乏的临床医生合作进行。如果我们的研究表明我们的假设是正确的，那么他们将改变临床医生治疗服用海普西丁的心力衰竭患者缺铁的方式。一种可能的改变是首先给这些患者服用降低海普西丁的化合物(这些药物已经在针对其他疾病的临床试验中进行测试)。降低海普西丁的好处是，它纠正了血液中的铁缺乏(通过清除肠道、肝脏和脾中的铁蛋白)，还恢复了心脏细胞控制其铁水平和避免铁毒性的能力(通过解除心脏中的铁蛋白)。

Iron is essential for life. It is required not only for the synthesis of haemoglobin, which carries oxygen around our bodies, but also for the function of the enzymes that generate energy inside our cells. Indeed, iron deficiency reduces exercise capacity, even when haemoglobin levels are normal. At the same time, too much iron within the cells is toxic because it promotes the production of damaging oxidants. Therefore, the control of iron levels is essential for the healthy functioning of our tissues. Tissues get their iron from the blood. Iron in the blood comes from three different sources; the spleen where iron is recycled from old blood cells, the liver where iron is stored, and the gut where iron is absorbed from the diet. Iron is exported from these organs into the blood by an iron-exporting protein called ferroportin. When iron levels in the blood get too high, the liver produces a hormone called hepcidin that blocks ferroportin so that blood iron levels return to normal. Inflammation also stimulates the production of hepcidin. Because of this, many patients with inflammatory conditions like heart disease and kidney disease have too much hepcidin in their blood. This inhibits the absorption of iron from the gut and causes iron to be locked inside the liver and the spleen. This is why many patients with chronic conditions have low iron levels in the blood and are described as "iron-deficient". In recent years, studies in these patients have shown that this iron deficiency worsens heart failure and increases mortality. There are now many efforts directed at finding the best way to treat this iron deficiency. Giving these patients oral iron does not work because iron absorption in the gut is blocked by hepcidin. A new treatment involving direct infusion of iron into the blood (by intravenous means) has been developed and rolled out to treat iron deficiency in patients with heart disease. In the past 5 years, work in my lab has discovered that heart cells use ferroprotin to control the amount of iron inside them. When we made mice that lacked ferroportin just in the heart, but had intact ferroportin in the gut, spleen and liver, these mice developed fatal heart failure because of too much iron being retained in heart cells. Like ferroportin at other sites, ferroportin in the heart can also be blocked by hepcidin. Based on this discovery, we hypothesise that high levels of hepcidin in patients also block ferroportin in heart cells, causing iron to be retained in the heart. When iron availability in the blood is low, this iron retention could protect the heart from becoming iron-depleted. However, when iron availability in the blood is high, especially after intravenous iron infusion, this retention could cause toxic iron accumulation in the heart. The aim of the research is to test this hypothesis. We will do this using both a mouse model of heart failure and human samples. The research will be conducted at the University of Oxford by my team in collaboration with clinicians who study and treat iron deficiency in heart failure patients. If our studies show that our hypothesis is true, then they will change how clinicians treat iron deficiency in heart failure patients who have raised hepcidin. One possible change is to give these patients compounds that lower hepcidin first (these are already being tested in clinical trials for other conditions). The advantage of lowering hepcidin is that it corrects iron deficiency in the blood (by unblocking ferroportin in the gut, liver and spleen) and also restores the ability of heart cells to control their iron levels and avoid iron toxicity (by unblocking ferroportin in the heart).