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

心脏铁调素/铁转运蛋白轴对心力衰竭缺铁治疗的影响

• 批准号: MR/V009567/1
• 负责人: Samira Lakhal-Littleton
• 金额: $ 251.01万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV009567%2F1
• 关键词: Implications; Cardiac; Hepcidin; Ferroportin; axis

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).

铁是生命所必需的。它不仅需要血红蛋白的合成，它在我们的身体中携带氧气，而且还需要在我们的细胞内产生能量的酶的功能。事实上，即使血红蛋白水平正常，缺铁也会降低运动能力。同时，细胞内过多的铁是有毒的，因为它促进了有害氧化剂的产生。因此，铁含量的控制对我们组织的健康运作至关重要。组织从血液中获取铁。血液中的铁有三个不同的来源；脾脏从老血细胞中回收铁，肝脏储存铁，肠道从饮食中吸收铁。铁通过一种叫做铁转运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，肝脏会产生一种叫做hepcidin的激素，这种激素会阻止铁转运蛋白，从而使血液中的铁含量恢复正常。炎症也刺激hepcidin的产生。正因为如此，许多患有心脏病和肾病等炎症的患者血液中含有过多的hepcidin。这抑制了肠道对铁的吸收，导致铁被锁在肝脏和脾脏内。这就是为什么许多慢性疾病患者血液中的铁含量低，被描述为“缺铁”。近年来，对这些患者的研究表明，缺铁会加重心力衰竭，增加死亡率。现在有很多努力都在寻找治疗铁缺乏症的最佳方法。给这些病人口服铁不起作用，因为铁在肠道中的吸收被hepcidin阻断了。一种将铁直接输注到血液中的新疗法（通过静脉注射的方式）已经被开发出来，用于治疗心脏病患者的缺铁。在过去的5年里，我的实验室发现心脏细胞使用铁蛋白来控制它们体内的铁含量。当我们制造出只在心脏中缺乏铁转运蛋白，而在肠道、脾脏和肝脏中有完整的铁转运蛋白的小鼠时，这些小鼠因为在心脏细胞中保留了太多的铁而患上了致命的心力衰竭。像其他位置的铁转运蛋白一样，心脏中的铁转运蛋白也可以被hepcidin阻断。基于这一发现，我们假设患者体内高水平的hepcidin也会阻断心脏细胞中的铁转运蛋白，导致铁保留在心脏中。当血液中的铁含量较低时，这种铁潴留可以保护心脏免于缺铁。然而，当血液中铁的可用性很高时，特别是在静脉输注铁后，这种保留可能导致有毒的铁在心脏中积聚。这项研究的目的是验证这一假设。我们将使用心力衰竭的小鼠模型和人类样本来做这个实验。这项研究将在牛津大学进行，由我的团队与研究和治疗心力衰竭患者缺铁的临床医生合作。如果我们的研究表明我们的假设是正确的，那么它们将改变临床医生治疗hepcidin升高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提供降低肝磷脂水平的化合物（这些化合物已经在其他疾病的临床试验中进行了测试）。降低hepcidin的好处是，它纠正了血液中的铁缺乏症（通过疏通肠道、肝脏和脾脏中的铁转运蛋白），也恢复了心脏细胞控制铁水平的能力，避免了铁中毒（通过疏通心脏中的铁转运蛋白）。

项目成果

Protective Role for Smooth Muscle Cell Hepcidin in Abdominal Aortic Aneurysm.

• DOI: 10.1161/atvbaha.123.319224
• 发表时间: 2023-05
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Loick, Paul;Mohammad, Goran Hamid;Cassimjee, Ismail;Chandrashekar, Anirudh;Lapolla, Pierfrancesco;Carrington, Alison;Vera-Aviles, Mayra;Handa, Ashok;Lee, Regent;Lakhal-Littleton, Samira
• 通讯作者: Lakhal-Littleton, Samira

Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells.

• DOI: 10.1038/s42255-021-00406-7
• 发表时间: 2021-07
• 期刊: Nature metabolism
• 影响因子: 20.8
• 作者: Schwartz AJ;Goyert JW;Solanki S;Kerk SA;Chen B;Castillo C;Hsu PP;Do BT;Singhal R;Dame MK;Lee HJ;Spence JR;Lakhal-Littleton S;Vander Heiden MG;Lyssiotis CA;Xue X;Shah YM
• 通讯作者: Shah YM

Minimal effect of conditional ferroportin KO in the neural retina implicates ferrous iron in retinal iron overload and degeneration.

• DOI: 10.1016/j.exer.2022.108988
• 发表时间: 2022-05
• 期刊: EXPERIMENTAL EYE RESEARCH
• 影响因子: 3.4
• 作者: Liu, Yingrui;Baumann, Bailey;Song, Ying;Zhang, Kevin;Sterling, Jacob K.;Lakhal-Littleton, Samira;Kozmik, Zbynek;Su, Guanfang;Dunaief, Joshua L.
• 通讯作者: Dunaief, Joshua L.

Low Serum Ferritin Might Predict Incident Heart Failure: But Why and Is It Clinically Useful?

低血清铁蛋白可能预测心力衰竭的发生：但为什么以及它在临床上有用吗？

• DOI: 10.1016/j.jchf.2023.12.012
• 发表时间: 2024
• 期刊: JACC. Heart failure
• 作者: Cleland JGF

PROTECTIVE ROLE FOR SMOOTH MUSCLE CELL HEPCIDIN IN ABDOMINAL AORTIC ANEURYSM

• DOI: 10.1101/2021.07.30.454447
• 发表时间: 2021-07
• 期刊: bioRxiv
• 作者: P. Loick;G. Mohammad;I. Cassimjee;A. Chandrashekar;P. Lapolla;A. Carrington;A. Handa;R. Lee;S. Lakhal-Littleton