Iron and oxidative stress in cardiomyopathy in thalassemia
Iron and oxidative stress in cardiomyopathy in thalassemia
复制标题
DOI：
10.1016/j.freeradbiomed.2015.07.019
复制
发表时间：
2015-11-01
影响因子：
7.4
通讯作者：
Cabantchik, Zvi Ioav
中科院分区：
文献类型：
--
作者：
Berdoukas, Vasilios;Coates, Thomas D.;Cabantchik, Zvi Ioav
随着反复输血，重型地中海贫血患者迅速变得铁负荷，通常超过铁蛋白壳内的肝脏金属积累能力，并浸润心脏和内分泌器官。该病理情况与生理情况形成对比，生理情况的特征在于有效维持与循环转铁蛋白结合的所有血浆铁，这是由于激素铁调素对铁进入血浆的严格控制。在细胞内，大多数获得的铁变成蛋白质相关的，因为一旦从内吞的转铁蛋白释放，它就在线粒体内用于蛋白质辅基的合成，或者它被掺入酶活性中心，或者被隔离在铁蛋白壳内。少数细胞类型还表达铁挤压转运蛋白ferroportin，其在循环铁调素的负控制下。然而，该系统仅支持主要细胞调节的铁摄取/储存机制，该机制准备维持不稳定细胞铁的基础水平以用于代谢目的，而不会引起潜在的毒性情况。在地中海贫血和其他输血铁负荷条件下，一旦转铁蛋白饱和度超过约70%，不稳定形式的铁进入循环，并可以通过常驻转运蛋白或通道进入各种类型的细胞。在细胞内，它们可以达到超过其化学科普不稳定铁的能力的水平，不稳定铁具有产生活性氧（ROS）的倾向，从而诱导氧化损伤。这种情况发生在没有接受足够的铁螯合治疗的重型地中海贫血患者的心脏中。在心肌细胞中积累的铁形成通过T2* MRI检测到的团块。铁的不稳定形式渗透线粒体并通过诱导有害的ROS形成来损伤细胞，导致心力衰竭。在一些重型地中海贫血患者中，在强化铁螯合治疗后观察到的心功能障碍的非常快速的缓解被认为是由于氧化应激引起的心脏线粒体功能障碍的缓解或由于不稳定铁干扰通过心脏钙通道的钙通量的去除。事实上，改善发生在心脏铁负荷的总水平有任何显着改善之前。口服铁螯合剂去铁酮，由于其小尺寸和中性电荷，可明显进入细胞并螯合不稳定的铁，从而快速减少ROS的形成，允许更好的线粒体活性和改善的心脏功能。去铁酮也可以迅速改善心律失常的患者谁没有过多的心脏铁。它保持铁在含铁血黄素到铁蛋白到游离铁的方向上的通量，并且在存在其他铁螯合剂或单独使用时允许清除心脏铁。迄今为止，最常用的螯合剂联合治疗是去铁胺加去铁酮，而其他组合正在评估过程中。总之，重型地中海贫血患者必须在其循环中持续存在铁螯合剂，以防止心脏暴露于不稳定铁，减少心脏毒性，改善心脏功能。(C)2015 Elsevier Inc. All rights reserved.
With repeated blood transfusions, patients with thalassemia major rapidly become loaded with iron, often surpassing hepatic metal accumulation capacity within ferritin shells and infiltrating heart and endocrine organs. That pathological scenario contrasts with the physiological one, which is characterized by an efficient maintenance of all plasma iron bound to circulating transferrin, due to a tight control of iron ingress into plasma by the hormone hepcidin. Within cells, most of the acquired iron becomes protein-associated, as once released from endocytosed transferrin, it is used within mitochondria for the synthesis of protein prosthetic groups or it is incorporated into enzyme active centers or alternatively sequestered within ferritin shells. A few cell types also express the iron extrusion transporter ferroportin, which is under the negative control of circulating hepcidin. However, that system only backs up the major cell regulated iron uptake/storage machinery that is poised to maintain a basal level of labile cellular iron for metabolic purposes without incurring potentially toxic scenarios. In thalassemia and other transfusion iron-loading conditions, once transferrin saturation exceeds about 70%, labile forms of iron enter the circulation and can gain access to various types of cells via resident transporters or channels. Within cells, they can attain levels that exceed their ability to chemically cope with labile iron, which has a propensity for generating reactive oxygen species (ROS), thereby inducing oxidative damage. This scenario occurs in the heart of hypertransfused thalassemia major patients who do not receive adequate iron-chelation therapy. Iron that accumulates in cardiomyocytes forms agglomerates that are detected by T2* MRI. The labile forms of iron infiltrate the mitochondria and damage cells by inducing noxious ROS formation, resulting in heart failure. The very rapid relief of cardiac dysfunction seen after intensive iron-chelation therapy in some patients with thalassemia major is thought to be due to the relief of the cardiac mitochondrial dysfunction caused by oxidative stress or to the removal of labile iron interference with calcium fluxes through cardiac calcium channels. In fact, improvement occurs well before there is any significant improvement in the total level of cardiac iron loading. The oral iron chelator deferiprone, because of its small size and neutral charge, demonstrably enters cells and chelates labile iron, thereby rapidly reducing ROS formation, allowing better mitochondrial activity and improved cardiac function. Deferiprone may also rapidly improve arrhythmias in patients who do not have excessive cardiac iron. It maintains the flux of iron in the direction hemosiderin to ferritin to free iron, and it allows clearance of cardiac iron in the presence of other iron chelators or when used alone. To date, the most commonly used chelator combination therapy is deferoxamine plus deferiprone, whereas other combinations are in the process of assessment. In summary, it is imperative that patients with thalassemia major have iron chelators continuously present in their circulation to prevent exposure of the heart to labile iron, reduce cardiac toxicity, and improve cardiac function. (C) 2015 Elsevier Inc. All rights reserved.