Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia
Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia
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DOI：
10.1080/14734220600913246
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发表时间：
2006-01-01
期刊：
影响因子：
3.5
通讯作者：
Koeppen, Arnulf H.
中科院分区：
文献类型：
--
作者：
Michael, Susan;Petrocine, Simone V.;Koeppen, Arnulf H.
肥厚型心肌病是弗里德赖希共济失调（FRDA）的常见并发症。组织切片显示异常心肌细胞、肌纤维坏死、反应性炎症和肌内膜结缔组织增加。散在的肌纤维显示肌原纤维之间成行排列的微小铁阳性颗粒的核周集合。FRDA中Frataxin缺乏导致线粒体铁代谢异常。我们研究了总铁和铁相关蛋白铁蛋白，线粒体铁蛋白，二价金属转运蛋白1（DMTI），和ferroportin在FRDA心脏的生化和组织学技术。FRDA患者左心室壁的总铁（30.7 +/- 19.3 mg/100 g干重）并不显著高于正常（31.3 +/- 24.1 mg/100 g干重）。类似地，FRDA心脏中的细胞溶质全铁蛋白水平（230 +/-172 μ g/g湿重）没有显著升高到高于正常水平（148 +/-86 μ g/g湿重）。铁阳性颗粒表现出免疫反应的胞浆铁蛋白，线粒体铁蛋白，和ferroportin。电子显微镜显示增强的电子密度的线粒体沉积物处理后，支持铁蛋白积累的次硝酸铋。肌内膜中的炎性细胞对CD 68、胞浆铁蛋白和从含有铁响应元件（DMT 1+）的信使核糖核酸翻译的DMT 1亚型具有反应性。FRDA中的进行性心肌病可能是铁催化的线粒体损伤，随后是肌纤维坏死和慢性反应性心肌炎的结果。
Hypertrophic cardiomyopathy is a common complication of Friedreich's ataxia (FRDA). Histological sections reveal abnormal cardiomyocytes, muscle fiber necrosis, reactive inflammation, and increased endomysial connective tissue. Scattered muscle fibers display perinuclear collections of minute iron-positive granules that lie in rows between myofibrils. Frataxin deficiency in FRDA causes mitochondrial iron dysmetabolism. We studied total iron and the iron-related proteins ferritin, mitochondrial ferritin, divalent metal transporter 1 (DMTI), and ferroportin in FRDA hearts by biochemical and histological techniques. Total iron in the left ventricular wall of FRDA patients (30.7 +/- 19.3 mg/100 g dry weight) was not significantly higher than normal (31.3 +/- 24.1 mg/100 g dry weight). Similarly, cytosolic holoferritin levels in FRDA hearts (230 +/- 172 mu g/g wet weight) were not significantly elevated above normal (148 +/- 86 mu g/g wet weight). The iron-positive granules exhibited immunoreactivity for cytosolic ferritin, mitochondrial ferritin, and ferroportin. Electron microscopy showed enhanced electron density of mitochondrial deposits after treatment with bismuth subnitrate supporting ferritin accumulation. The inflammatory cells in the endomysium were reactive for CD68, cytosolic ferritin, and the DMT1 isoform(s) translated from messenger ribonucleic acids containing iron-responsive elements (DMT1+). Progressive cardiomyopathy in FRDA is the likely result of iron-catalyzed mitochondrial damage followed by muscle fiber necrosis and a chronic reactive myocarditis.