Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischaemia/reperfusion injury
Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischaemia/reperfusion injury
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DOI：
10.1093/cvr/cvs332
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发表时间：
2013-02-01
影响因子：
10.8
通讯作者：
Shimizu, Shunichi
中科院分区：
文献类型：
--
作者：
Hiroi, Toshihito;Wajima, Teruaki;Shimizu, Shunichi
瞬时受体电位melastatin 2（TRPM 2）是一种在氧化应激条件下激活的钙离子通道，在免疫细胞中高表达。心肌缺血/再灌注（I/R）损伤的特征是与氧化应激增强相关的急性炎症。我们假设TRPM 2参与了心肌I/R损伤的加重。野生型（Trpm 2（/））和Trpm 2基因敲除（Trpm 2（/））小鼠进行左冠状动脉主干结扎后再灌注。与Trpm 2（/）小鼠相比，Trpm 2（/）小鼠I/R后心肌梗死的减少更多，而不是单纯缺血，Trpm 2（/）小鼠的心脏收缩功能也得到改善。TRPM 2在多形核白细胞（PMN）中高度表达，而不是在心脏中。Trpm 2（/）小鼠缺血后再灌注区中性粒细胞数量和髓过氧化物酶（MPO）活性降低。将Trpm 2（/）或Trpm 2（/）PMNs通过离体灌流液或在体静脉注射给予Trpm 2（/）心脏后，Trpm 2（/）PMNs引起梗死面积增大。在体外局部I/R后，TRPM 2的药理学抑制剂减少了梗死面积。过氧化氢和白三烯B-4（LTB 4）联合作用可增加Trpm 2（/）中性粒细胞内Ca-2浓度及其与内皮细胞的粘附，但对Trpm 2（/）中性粒细胞无影响，提示中性粒细胞TRPM 2参与了心肌再灌注损伤的加重。TRPM 2激活介导的再灌注区中性粒细胞的积聚可能在心肌I/R损伤中起关键作用。
Transient receptor potential melastatin 2 (TRPM2) highly expressed in immunocytes is a Ca-2-permeable non-selective cation channel activated by oxidative stress. Myocardial ischaemia/reperfusion (I/R) injury is characterized by acute inflammation associated with the augmentation of oxidative stress. We hypothesized that TRPM2 is implicated in the exacerbation of myocardial I/R injury.Wild-type (Trpm2(/)) and Trpm2 knockout (Trpm2(/)) mice were subjected to ligation of the left main coronary artery followed by reperfusion. Myocardial infarction following I/R, but not ischaemia alone, was reduced more in Trpm2(/)mice than in Trpm2(/) mice and cardiac contractile functions were also improved in Trpm2(/)mice. TRPM2 was highly expressed in the polymorphonuclear leucocytes (PMNs) rather than in the heart. The number of neutrophils and myeloperoxidase (MPO) activity in the reperfused area following ischaemia was lowered in Trpm2(/) mice. When Trpm2(/) or Trpm2(/) PMNs were administered to the Trpm2(/) heart ex vivo through the perfusate or in vivo by iv injection, Trpm2(/) PMNs produced enlargement of the infarct size. Following in vitro regional I/R, a pharmacological inhibitor of TRPM2 reduced the infarct size. The combination of H2O2 and leukotriene B-4 (LTB4) increased intracellular Ca-2 concentration and their adhesion to endothelial cells in Trpm2(/) but not in Trpm2(/)PMNs.These findings indicate that neutrophil TRPM2 is implicated in the exacerbation of myocardial reperfusion injury. Accumulation of neutrophils in the reperfused area mediated by TRPM2 activation is likely to play a crucial role in myocardial I/R injury.