预处理可延迟钙离子诱导的线粒体通透性转换。

Preconditioning delays Ca2+-induced mitochondrial permeability transition.

作者信息

Argaud Laurent, Gateau-Roesch Odile, Chalabreysse Lara, Gomez Ludovic, Loufouat Joseph, Thivolet-Béjui Françoise, Robert Dominique, Ovize Michel

机构信息

INSERM E0226, Laboratoire de Physiologie Lyon-Nord, Université Claude Bernard Lyon I, 8, Avenue Rockefeller, 69373 Lyon, France.

出版信息

Cardiovasc Res. 2004 Jan 1;61(1):115-22. doi: 10.1016/j.cardiores.2003.11.003.

DOI:10.1016/j.cardiores.2003.11.003

PMID:14732208

Abstract

OBJECTIVE

We investigated whether ischemic preconditioning (PC) may modify mitochondrial permeability transition (MPT) pore opening.

METHODS

In protocol 1, New Zealand White rabbits underwent either no intervention (sham group) or 10 min of ischemia followed by 5 min of reperfusion, preceded (PC) or not (C; control) by one episode of 5 min of ischemia and 5 min of reperfusion. Rabbits were pretreated by either saline or the MPT pore inhibitor cyclosporin A (CsA), or its non-immunosuppressive derivative Cs29 (10 mg/kg, IV bolus). Hearts were harvested and mitochondria isolated for further assessment of Ca(2+)-induced MPT using a Ca(2+)-sensitive micro-electrode. In protocol 2, C and PC hearts underwent 30 min of ischemia and 4 h of reperfusion. They were pretreated either by saline, CsA or Cs29, as in protocol 1. Infarct size was assessed by triphenyltetrazolium, and apoptosis by TUNEL staining.

RESULTS

In protocol 1, the Ca(2+) overload required to induce MPT pore opening was significantly higher in PC than in C hearts. CsA and Cs29 significantly increased the Ca(2+) overload required for MPT pore opening. In protocol 2, mean infarct size averaged 25% of the risk region in CsA/Cs29 treated hearts versus 15% in PC and 55% in controls (P<0.05 vs. C, P=ns vs. PC). Cardiomyocyte apoptosis was significantly reduced by PC and cyclosporin treatment with a mean apoptotic index of less than 2% in either group versus more than 11% in controls.

CONCLUSION

This suggests that delayed opening of MPT pore may play a major role in ischemic PC.

摘要

目的

我们研究了缺血预处理（PC）是否可能改变线粒体通透性转换（MPT）孔的开放。

方法

在方案1中，新西兰白兔要么不进行干预（假手术组），要么经历10分钟缺血，随后5分钟再灌注，在这之前（PC组）或不进行（C组；对照组）5分钟缺血和5分钟再灌注的预处理。兔子分别用生理盐水、MPT孔抑制剂环孢素A（CsA）或其非免疫抑制衍生物Cs29（10mg/kg，静脉推注）进行预处理。收获心脏并分离线粒体，使用钙敏感微电极进一步评估钙诱导的MPT。在方案2中，C组和PC组心脏经历30分钟缺血和4小时再灌注。如方案1中一样，它们分别用生理盐水、CsA或Cs29进行预处理。通过三苯基四氮唑评估梗死面积，通过TUNEL染色评估细胞凋亡。

结果

在方案1中，诱导MPT孔开放所需的钙超载在PC组心脏中显著高于C组心脏。CsA和Cs29显著增加了MPT孔开放所需的钙超载。在方案2中，在CsA/Cs29处理的心脏中，平均梗死面积平均为危险区域的25%，而在PC组中为15%，在对照组中为55%（与C组相比P<0.05，与PC组相比P=无显著差异）。PC和环孢素治疗显著减少了心肌细胞凋亡，两组的平均凋亡指数均小于2%，而对照组则超过11%。