PDF(Pubmed)
Abstract：
Elevated intracellular sodium Nai adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Nai decreases Gibb\'s free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH2, which are all reversed on lowering Nai to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Nai elevation. Elevated Nai plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.
摘要：
细胞内钠的升高会对线粒体代谢产生不利影响，并且是心力衰竭的常见特征。在Langendorff灌注的大鼠心脏中，使用Na/KATPase抑制剂ouabain和肌球蛋白解偶联剂对氨基blebistatin维持恒定的能量需求，评估了急性Na诱导的代谢变化的可逆性。升高的Nai降低了Gibb的ATP水解自由能，增加TCA循环中间体琥珀酸酯和富马酸酯，降低复合物I的ETC活性，II和III,并导致CoQ的氧化还原转变为CoQH2，这在将Nai降低至基线水平时全部逆转。尽管组织氧合正常，但仍观察到HIF-1α的假性缺氧和稳定。用CGP-37517抑制线粒体Na/Ca交换或用线粒体ROS清除剂MitoQ治疗可防止Nai升高期间的代谢改变。升高的Nai在代谢和功能变化中起着可逆的作用，并且是纠正心力衰竭中代谢功能障碍的新治疗靶标。
