Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection
Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection
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DOI：
10.1042/cs20080523
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发表时间：
2009-09-01
期刊：
影响因子：
6
通讯作者：
Redington, Andrew N.
中科院分区：
文献类型：
--
作者：
Shimizu, Mikiko;Tropak, Michael;Redington, Andrew N.
rIPC（远程缺血预处理）是组织或器官（例如肠系膜、肾）的短期缺血和再灌注可以保护远端组织或器官（例如心脏）免受随后的潜在致死性缺血的现象。我们和其他人已经证明，在实验和临床上，短暂的肢体缺血可以在心脏手术中提供有效的心肌保护。然而，我们对从远程刺激到局部效应的信号转导的理解仍然是不完整的。本研究的目的是确定肢体缺血rIPC效应物的体液性质，并研究其在离体心脏和心肌细胞模型中的局部作用。使用Langendorff制剂，我们表明，在体内冠状动脉结扎和再灌注后的梗死面积大大减少rIPC，这种刺激上调MAPK（丝裂原活化蛋白激酶）p42/p44，并诱导PKC β（蛋白激酶C β）亚细胞再分布。用来自接受rIPC的供体兔的血浆和血浆透析液（使用15 kDa截留透析膜获得）进行预处理，可类似地防止梗死。rIPC透析液的有效性通过C-18疏水柱而被消除，但来自该柱的洗脱液提供了相同水平的保护。还在模拟缺血和再灌注的分离的新鲜心肌细胞模型中测试来自兔和人的rIPC血浆的透析液。与对照组相比，用rIPC透析液处理的心肌细胞的坏死显著减少，并且与通过“经典”预处理预处理的细胞相似。这种作用，通过兔rIPC透析液，被阻断与阿片受体阻断剂纳洛酮预处理。总之，在体内短暂的肢体缺血释放低分子量（
rIPC (remote ischaemic preconditioning) is a phenomenon whereby short periods of ischaemia and reperfusion of a tissue or organ (e.g. mesentery, kidney) can protect a distant tissue or organ (e.g. heart) against subsequent, potentially lethal, ischaemia. We, and others, have shown that transient limb ischaemia can provide potent myocardial protection experimentally and clinically during cardiac surgery. Nonetheless, our understanding of the signal transduction from remote stimulus to local effect remains incomplete. The aim of the present study was to define the humoral nature of rIPC effector(s) from limb ischaemia and to study their local effects in isolated heart and cardiomyocyte models. Using a Langendorff preparation, we show that infarct size after coronary artery ligation and reperfusion was substantially reduced by rIPC in vivo, this stimulus up-regulating the MAPKs (mitogen-activating protein kinases) p42/p44, and inducing PKC epsilon (protein kinase C epsilon) subcellular redistribution. Pre-treatment with the plasma and dialysate of plasma (obtained using 15 kDa cut-off dialysis membrane) from donor rabbits subjected to rIPC similarly protected against infarction. The effectiveness of the rIPC dialysate was abrogated by passage through a C-18 hydrophobic column, but eluate from this column provided the same level of protection. The dialysate of rIPC plasma from rabbits and humans was also tested in an isolated fresh cardiomyocyte model of simulated ischaemia and reperfusion. Necrosis in cardiomyocytes treated with rIPC dialysate was substantially reduced compared with control, and was similar to cells pre-treated by 'classical' preconditioning. This effect, by rabbit rIPC dialysate, was blocked by pretreatment with the opiate receptor blocker naloxone. In conclusion, in vivo transient limb ischaemia releases a low-molecular-mass (