Cardiac Electrophysiology Research and Training Center, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Eur J Haematol. 2011 Feb;86(2):156-66. doi: 10.1111/j.1600-0609.2010.01549.x. Epub 2010 Dec 29.
Iron-overload condition can be found in β-thalassemic patients with regular blood transfusion, leading to iron deposition in various organs including the heart. Elevated cardiac iron causes iron-overload cardiomyopathy, a condition that provokes mortality because of heart failure in patients with thalassemia. Previous studies demonstrated that myocardial iron uptake may occur via L-type calcium channels (LTCCs). However, direct evidence regarding the claimed pathway in thalassemic cardiomyocytes has never been investigated.
Hearts from genetic-altered β-thalassemic mice and adult wild-type mice were used for cultured ventricular cardiomyocytes. Blockers for LTCC, T-type calcium channel (TTCC), transferrin receptor1 (TfR1), and divalent metal transporter1 (DMT1) were used, and quantification of cellular iron uptake under various iron loading conditions was performed by Calcein-AM fluorescence assay. Microarray analysis was performed to investigate gene expressions in the hearts of these mice.
This study demonstrated that iron uptake under iron-overload conditions in the cultured ventricular myocytes of thalassemic mice was greater than that of wild-type cells (P <0.01). TTCC blocker, efonidipine, and an iron chelator, deferoxamine, could prevent iron uptake into cultured cardiomyocytes, whereas blockers of TfR1, DMT1, and LTCC could not. Microarray analysis from thalassemic hearts demonstrated highly up-regulated genes of TTCC, zinc transporter, and transferrin receptor2.
Our findings indicated that iron uptake mechanisms in cultured thalassemic cardiomyocytes are mainly mediated by TTCC, suggesting that TTCC is the important pathway for iron uptake in this cultured thalassemic cardiomyocyte model.
β-地中海贫血患者经常接受输血治疗，会出现铁过载的情况，导致铁在包括心脏在内的各种器官中沉积。过量的心脏铁会导致铁过载性心肌病，这种疾病会导致地中海贫血患者因心力衰竭而死亡。先前的研究表明，心肌铁摄取可能通过 L 型钙通道（LTCC）发生。然而，关于地中海贫血心肌细胞中所声称的途径的直接证据从未被研究过。
使用基因改变的β-地中海贫血小鼠和成年野生型小鼠的心脏来培养心室心肌细胞。使用 LTCC、T 型钙通道（TTCC）、转铁蛋白受体 1（TfR1）和二价金属转运蛋白 1（DMT1）的阻滞剂，并通过 Calcein-AM 荧光测定法在各种铁负荷条件下对细胞内铁摄取进行定量。进行微阵列分析以研究这些小鼠心脏中的基因表达。
本研究表明，铁过载条件下培养的地中海贫血小鼠心室心肌细胞中的铁摄取量大于野生型细胞（P <0.01）。TTCC 阻滞剂依福地平（efonidipine）和铁螯合剂去铁胺（deferoxamine）可阻止铁进入培养的心肌细胞，而 TfR1、DMT1 和 LTCC 的阻滞剂则不能。从地中海贫血心脏的微阵列分析中，TTCC、锌转运体和转铁蛋白受体 2 的基因表达高度上调。
我们的研究结果表明，培养的地中海贫血心肌细胞中的铁摄取机制主要由 TTCC 介导，这表明 TTCC 是该培养的地中海贫血心肌细胞模型中铁摄取的重要途径。
