Khamseekaew Juthamas, Kumfu Sirinart, Wongjaikam Suwakon, Kerdphoo Sasiwan, Jaiwongkam Thidarat, Srichairatanakool Somdet, Fucharoen Suthat, Chattipakorn Siriporn C, Chattipakorn Nipon
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
Eur J Pharmacol. 2017 Mar 15;799:118-127. doi: 10.1016/j.ejphar.2017.02.015. Epub 2017 Feb 10.
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. β-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 (75mg/kg/day) or efonidipine (4mg/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.
尽管心脏线粒体功能障碍参与了铁过载性心肌病的病理生理过程，但铁诱导线粒体功能障碍的确切机制，以及铁螯合剂去铁酮和T型钙通道阻滞剂依福地平对地中海贫血小鼠心脏线粒体生物发生的作用仍不清楚。将β地中海贫血（HT）小鼠喂食正常饮食（ND）或高铁饮食（FE）90天。然后，对喂食FE的小鼠用去铁酮（75mg/kg/天）或依福地平（4mg/kg/天）治疗30天。取心脏用于测定心脏线粒体功能、生物发生、线粒体动力学以及氧化磷酸化（OXPHOS）和凋亡的蛋白质表达。与喂食ND的野生型小鼠相比，喂食ND的HT小鼠心率变异性（HRV）受损，线粒体动态蛋白和半胱天冬酶-3增加。铁过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，以及HRV和左心室功能受损、心脏线粒体功能和线粒体动力学受损，并且复合物IV减少。我们的结果表明，去铁酮和依福地平治疗在减轻心脏铁沉积和氧化应激方面显示出相似的益处，并改善了心脏线粒体功能，从而改善了左心室功能，而不会改变铁过载地中海贫血小鼠的心脏线粒体生物发生和凋亡蛋白。
