Heidbreder Marc, Naumann Annegret, Tempel Klaus, Dominiak Peter, Dendorfer Andreas
Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Cardiovasc Res. 2008 Apr 1;78(1):108-15. doi: 10.1093/cvr/cvm114. Epub 2007 Dec 20.
Since mitogen-activated protein kinases (MAPKs) were found to be implicated in the signalling of ischaemic preconditioning (IPC), we tested the hypothesis of a contribution of these protein kinases to remote preconditioning (RPC).
To determine the role of p38, ERK1/2, and JNK1/2 MAPKs in mediating cardiac protection, an in vivo model of myocardial infarction was applied in male Wistar rats. RPC or IPC was induced by occlusion of the superior mesenteric artery or the left coronary artery, respectively. Infarct size (IS) was determined based on 2,3,5-triphenyltetrazolium chloride staining. Phosphorylation of the various MAPKs was analysed by immunoblotting in samples of the small intestine and myocardium obtained after IPC or RPC procedures. The MAPK inhibitors SB203580 (p38), PD98059 (ERK1/2), and SP600125 (JNK1/2) were administered to assess the potential significance of MAPK signalling in RPC. Both preconditioning stimuli decreased myocardial IS significantly after a lethal period of ischaemia. Each of the applied MAPK inhibitors was capable of abrogating the RPC-induced cardioprotection. Western blot analysis of myocardial samples revealed an increase in phosphorylated amounts of ERK1/2 and JNK1 after IPC, whereas phosphorylation of p38 protein was decreased significantly. Likewise, RPC resulted in a considerable increase in phosphorylation of ERK1/2 and JNK1/2 proteins in the small intestine, whereas it did not alter the MAPK phosphorylation state in the myocardium.
All investigated MAPK pathways appear to be involved in RPC-induced cardioprotection; however, they do not contribute to the alterations that define the preconditioned state of the myocardium prior to the infarction.
由于发现丝裂原活化蛋白激酶（MAPKs）参与缺血预处理（IPC）信号传导，我们检验了这些蛋白激酶对远程预处理（RPC）有作用的假说。
为确定p38、ERK1/2和JNK1/2 MAPKs在介导心脏保护中的作用，在雄性Wistar大鼠中应用心肌梗死体内模型。RPC或IPC分别通过肠系膜上动脉或左冠状动脉闭塞诱导。基于2,3,5-三苯基氯化四氮唑染色确定梗死面积（IS）。通过免疫印迹分析在IPC或RPC程序后获得的小肠和心肌样本中各种MAPKs的磷酸化情况。给予MAPK抑制剂SB203580（p38）、PD98059（ERK1/2）和SP600125（JNK1/2）以评估MAPK信号传导在RPC中的潜在意义。两种预处理刺激在致死性缺血期后均显著降低心肌IS。每种应用的MAPK抑制剂都能够消除RPC诱导的心脏保护作用。心肌样本的蛋白质印迹分析显示IPC后ERK1/2和JNK1磷酸化量增加，而p38蛋白的磷酸化显著降低。同样，RPC导致小肠中ERK1/2和JNK1/2蛋白的磷酸化显著增加，而它并未改变心肌中的MAPK磷酸化状态。
所有研究的MAPK途径似乎都参与RPC诱导的心脏保护作用；然而，它们对梗死前心肌预处理状态的改变并无作用。
