Involvement of reperfusion injury salvage kinases in preconditioning depends critically on the preconditioning stimulus
Involvement of reperfusion injury salvage kinases in preconditioning depends critically on the preconditioning stimulus
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DOI：
10.1258/ebm.2011.010260
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发表时间：
2011-07
影响因子：
3.2
通讯作者：
O. Manintveld;W. Sluiter;D. Dekkers;Maaike te Lintel Hekkert;J. Lamers;P. Verdouw;D. Duncker
中科院分区：
文献类型：
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作者：
O. Manintveld;W. Sluiter;D. Dekkers;Maaike te Lintel Hekkert;J. Lamers;P. Verdouw;D. Duncker
不同的预处理刺激可以激活不同的信号通路。在大鼠中，存在腺苷非依赖性途径（三次3分钟冠状动脉闭塞[3CAO3]）和腺苷依赖性途径（一次15分钟冠状动脉闭塞[ICAO15]），两者最终在线粒体呼吸链水平趋同。此外，虽然3CAO3、1CAO15和外源性腺苷（ADO）同样具有心脏保护作用，但只有1CAO15增加了间质心肌腺苷水平。再灌注损伤挽救激酶（RISK）通路激酶与缺血预处理有关，但并非所有预处理刺激都激活该通路。因此，我们在麻醉大鼠中评估了三种截然不同的预处理刺激（3CAO3、1CAO15或ADO）对梗死面积（IS）、信号通路(特别强调属于RISK通路的激酶（磷脂酰肌醇3-激酶- akt -一氧化氮合酶和细胞外信号相关激酶[ERK]）和线粒体呼吸的影响。所有三种刺激都增加了状态2呼吸（使用琥珀酸盐作为复合物ii底物），从而降低了呼吸控制指数，这伴随着60分钟冠状动脉闭塞（CAO）产生的IS限制。一氧化氮合酶抑制可消除3CAO3、1CAO15或ADO的线粒体作用和心脏保护作用。相比之下，PI3激酶抑制剂wortmannin阻断了1CAO15的保护作用，但不影响3CAO3或ADO的保护作用。Western blotting证实，Akt和ERK的磷酸化被1CAO15 （wortmannin抑制）增加，而3CAO3或ADO则没有。综上所述，虽然三种心脏保护刺激3CAO3、1CAO15和ADO通过一氧化氮介导的线粒体呼吸调节来提供心脏保护，但只有1CAO15通过激活属于RISK途径的激酶来发挥其保护作用。
Different preconditioning stimuli can activate divergent signaling pathways. In rats, adenosine-independent pathways (triple 3-min coronary artery occlusion [3CAO3]) and adenosine-dependent pathways (one 15-min coronary artery occlusion [ICAO15]) exist, both ultimately converging at the level of the mitochondrial respiratory chain. Furthermore, while 3CAO3, 1CAO15 and exogenous adenosine (ADO) are equally cardioprotective, only 1CAO15 increases interstitial myocardial adenosine levels. Reperfusion Injury Salvage Kinase (RISK) pathway kinases have been implicated in ischemic preconditioning, but not all preconditioning stimuli activate this pathway. Consequently, we evaluated in anesthetized rats the effects of three distinctly different preconditioning stimuli (3CAO3, 1CAO15 or ADO) on infarct size (IS), signaling pathways with a special emphasis on kinases belonging to the RISK pathway (phosphatidylinositol 3-kinase-Akt-nitric oxide synthase and extracellular signal-related kinase [ERK]) and mitochondrial respiration. All three stimuli increased state-2 respiration (using succinate as complex-II substrate), thereby decreasing the respiratory control index, which was accompanied by a limitation of IS produced by a 60-min coronary artery occlusion (CAO). Nitric oxide synthase inhibition abolished the mitochondrial effects and the cardioprotection by 3CAO3, 1CAO15 or ADO. In contrast, the PI3 kinase inhibitor, wortmannin, blocked protection by 1CAO15, but did not affect protection by 3CAO3 or ADO. Western blotting confirmed that phosphorylation of Akt and ERK were increased by 1CAO15 (which was inhibited by wortmannin), but not by 3CAO3 or ADO. In conclusion, while the three cardioprotective stimuli 3CAO3, 1CAO15 and ADO afford cardioprotection via nitric oxide-mediated modulation of mitochondrial respiration, only the 1CAO15 exerts its protection via activation of kinases belonging to the RISK pathway.