Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041, China.
Exp Biol Med (Maywood). 2018 May;243(9):780-785. doi: 10.1177/1535370218773055.
The distribution of copper (Cu) in the biological system is regulated by Cu transporters and chaperones. It has been known for a long time that myocardial ischemia is accompanied by the loss of Cu from the heart, but the mechanism by which this occurs remains unknown. The present study was undertaken to understand the relationship between Cu loss and alterations in Cu transporters during the pathogenesis of myocardial ischemia. Male mice (C57 BL/6J) were subjected to left anterior descending (LAD) coronary artery ligation to induce myocardial ischemia. Changes in Cu concentrations in serum and hearts were determined from blood and tissue samples harvested at different time points for a total of 28 days after the operation. Cu concentrations in the ischemic myocardium were continuously decreased starting at the fourth day after LAD artery ligation, gradually depleted by more than 80% of the normal level at the 10th day, and remained at the lowest level (about 20% of normal levels) thereafter. Serum Cu concentrations were correspondingly increased starting at the fourth day, reached to the highest level between day 7 and 10, and gradually recovered to the normal level until 21st day after the operation. Along with the same time course, the intracellular Cu exporter copper metabolism MURR domain 1 (COMMD1) was significantly and sustainably increased, but ATP7A and ATP7B were not significantly changed in the ischemic myocardium. These results suggest that during the pathogenesis of myocardial ischemia, COMMD1 would play a critical role in exporting Cu from the ischemic myocardium to the blood. Impact statement In this work, we found that copper efflux from the ischemic heart leads to the elevation of serum copper concentrations, addressing a long-term question related to serum copper elevation in myocardial ischemia patients. The efflux of copper from the ischemic heart results at least in part from the upregulation of copper metabolism MURR domain 1 (COMMD1) in the heart upon ischemic insult. This work provides a novel insight into copper homeostasis and alteration in cardiovascular system.
铜（Cu）在生物系统中的分布受 Cu 转运蛋白和伴侣蛋白的调节。长期以来，人们一直知道心肌缺血伴随着 Cu 从心脏中丢失，但发生这种情况的机制尚不清楚。本研究旨在了解 Cu 丢失与心肌缺血发病过程中 Cu 转运蛋白改变之间的关系。雄性小鼠（C57BL/6J）接受左前降支（LAD）冠状动脉结扎以诱导心肌缺血。从手术后不同时间点采集的血液和组织样本中测定血清和心脏中 Cu 浓度，总共 28 天。从 LAD 动脉结扎后第四天开始，缺血心肌中的 Cu 浓度持续下降，第 10 天逐渐减少到正常水平的 80%以上，此后一直保持在最低水平（约为正常水平的 20%）。血清 Cu 浓度从第四天开始相应增加，在第 7 天至第 10 天之间达到最高水平，然后逐渐恢复到正常水平，直到手术后第 21 天。随着相同的时间进程，细胞内 Cu 外排蛋白铜代谢 MURR 结构域 1（COMMD1）显著且持续增加，但缺血心肌中的 ATP7A 和 ATP7B 没有明显变化。这些结果表明，在心肌缺血发病过程中，COMMD1 将在 Cu 从缺血心肌向血液中输出中发挥关键作用。
影响声明在这项工作中，我们发现缺血心脏中 Cu 的外排导致血清铜浓度升高，解决了与心肌缺血患者血清铜升高相关的一个长期问题。缺血损伤导致缺血心脏中铜代谢 MURR 结构域 1（COMMD1）的上调，至少部分导致了缺血心脏中铜的外排。这项工作为铜稳态和心血管系统的改变提供了新的见解。
