Effects of iron overload, an iron chelator and a T-Type calcium channel blocker on cardiac mitochondrial biogenesis and mitochondrial dynamics in thalassemic mice
Effects of iron overload, an iron chelator and a T-Type calcium channel blocker on cardiac mitochondrial biogenesis and mitochondrial dynamics in thalassemic mice
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DOI：
10.1016/j.ejphar.2017.02.015
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发表时间：
2017-03-15
影响因子：
5
通讯作者：
Chattipakorn, Nipon
中科院分区：
文献类型：
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作者：
Khamseekaew, Juthamas;Kumfu, Sirinart;Chattipakorn, Nipon
虽然心脏线粒体功能障碍参与了铁超载心肌病的病理生理学，但铁诱导的线粒体功能障碍的确切机制，以及铁螯合剂去铁酮和T型钙通道阻滞剂依非地平对地中海贫血小鼠心脏线粒体生物合成的作用仍然未知。用正常饮食（ND）或高铁饮食（FE）喂养β-地中海贫血（HT）小鼠90天。然后，用去铁酮（75 mg/kg/天）或依福地平（4 mg/kg/天）治疗FE喂养的小鼠30天。心脏用于测定心脏线粒体功能、生物发生、线粒体动力学和氧化磷酸化（OXPHOS）和凋亡的蛋白表达。与ND喂养的野生型小鼠相比，ND喂养的HT小鼠心率变异性（HRV）受损，线粒体动态蛋白和caspase-3增加。铁超载导致地中海贫血小鼠血浆非转铁蛋白结合铁增加，氧化应激，HRV和左心室功能，心脏线粒体功能和线粒体动力学的损害，并减少复合物IV。我们的研究结果表明，去铁酮和依非地平治疗在减轻心脏铁存款和氧化应激方面表现出相似的益处，并改善心脏线粒体功能，从而改善左心室功能，而不改变铁超载地中海贫血小鼠的心脏线粒体生物合成和凋亡蛋白。
Although cardiac mitochondrial dysfunction is involved in the pathophysiology of iron-overload cardiomyopathy, the precise mechanisms of iron-induced mitochondrial dysfunction, and the roles of the iron chelator deferiprone and the T-type calcium channel blocker efonidipine on cardiac mitochondrial biogenesis in thalassemic mice are still unknown. beta-thalassemic (HT) mice were fed with a normal diet (ND) or a high iron diet (FE) for 90 days. Then, the FE-fed mice were treated with deferiprone (75 mg/kg/day) or efonidipine (4 mg/kg/day) for 30 days. The hearts were used to determine cardiac mitochondrial function, biogenesis, mitochondrial dynamics and protein expressions for oxidative phosphorylation (OXPHOS) and apoptosis. ND fed HT mice had impaired heart rate variability (HRV), increased mitochondrial dynamic proteins and caspase-3, compared with ND-fed wild-type mice. Iron overload led to increased plasma non-transferrin bound iron, oxidative stress, and the impairments of HRV and left ventricular function, cardiac mitochondrial function and mitochondrial dynamics, and decreased complex IV in thalassemic mice. Our results suggested that deferiprone and efonidipine treatment showed similar benefit in attenuating cardiac iron deposit and oxidative stress, and improved cardiac mitochondrial function, leading to improved left ventricular function, without altering the cardiac mitochondrial biogenesis, and apoptosis proteins in iron-overload thalassemic mice.