Cardiac-specific ablation of the Na+-Ca2+ exchanger confers protection against ischemia/reperfusion injury
Cardiac-specific ablation of the Na+-Ca2+ exchanger confers protection against ischemia/reperfusion injury
复制标题
DOI：
10.1161/01.res.0000187456.06162.cb
复制
发表时间：
2005-10-28
影响因子：
20.1
通讯作者：
Murphy, E
中科院分区：
文献类型：
--
作者：
Imahashi, K;Pott, C;Murphy, E
在缺血再灌流过程中，随着细胞内Na+浓度的增加和膜电位的去极化，钙离子可能通过反向Na+-钙离子交换(NCX)进入心肌细胞以换取细胞内的Na+。为了测试NCX在缺血和再灌注过程中钙离子内流的作用，我们研究了心脏特异性消融NCX(NCX-KO)的小鼠，发现NCX-KO的心肌细胞不存在反向模式的钙内流。在此期间，我们用P-31-核磁共振仪监测高能磷酸盐和左心室发展压。在另一组心脏中，我们使用Na-23-核磁共振监测细胞内的Na+。与缺血期间通过NCX进入的钙离子相一致，我们发现缺乏NCX的心脏在缺血期间表现出较少的ATP下降，延迟的缺血性收缩，以及最大收缩减少。此外，在缺血再灌流时，NCX-KO组心肌坏死明显减少，左心室发展压恢复较好，磷酸肌酸恢复较好，Na+超载减少。NCX-KO心脏缺血后功能恢复的改善并不归因于NCX-KO心脏缺血前收缩能力的降低，因为当缺血前工作量与异丙肾上腺素治疗相匹配时，与野生型心脏相比，NCX-KO心脏仍然表现出更好的缺血后功能。因此，NCX-KO心脏对缺血再灌注损伤有明显的保护作用，提示NCX通过反向模式的钙离子内流是造成缺血/再灌注损伤的主要原因。
During ischemia and reperfusion, with an increase in intracellular Na+ and a depolarized membrane potential, Ca2+ may enter the myocyte in exchange for intracellular Na+ via reverse-mode Na+-Ca2+ exchange (NCX). To test the role of Ca2+ entry via NCX during ischemia and reperfusion, we studied mice with cardiac-specific ablation of NCX (NCX-KO) and demonstrated that reverse-mode Ca2+ influx is absent in the NCX-KO myocytes. Langendorff perfused hearts were subjected to 20 minutes of global ischemia followed by 2 hours of reperfusion, during which time we monitored high-energy phosphates using P-31-NMR and left-ventricular developed pressure. In another group of hearts, we monitored intracellular Na+ using Na-23-NMR. Consistent with Ca2+ entry via NCX during ischemia, we found that hearts lacking NCX exhibited less of a decline in ATP during ischemia, delayed ischemic contracture, and reduced maximum contracture. Furthermore, on reperfusion following ischemia, NCX-KO hearts had much less necrosis, better recovery of left-ventricular developed pressure, improved phosphocreatine recovery, and reduced Na+ overload. The improved recovery of function following ischemia in NCX-KO hearts was not attributable to the reduced preischemic contractility in NCX- KO hearts, because when the preischemic workload was matched by treatment with isoproterenol, NCX-KO hearts still exhibited improved postischemic function compared with wild-type hearts. Thus, NCX- KO hearts were significantly protected against ischemia-reperfusion injury, suggesting that Ca2+ entry via reverse-mode NCX is a major cause of ischemia/reperfusion injury.