Involvement of glycogen synthase kinase-3 beta in liver ischemic conditioning induced cardioprotection against myocardial ischemia and reperfusion injury in rats
Involvement of glycogen synthase kinase-3 beta in liver ischemic conditioning induced cardioprotection against myocardial ischemia and reperfusion injury in rats
复制标题
糖原合酶激酶3β参与肝脏缺血调理诱导的大鼠心肌缺血再灌注损伤的心脏保护作用
DOI：
10.1152/japplphysiol.00862.2016
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发表时间：
2017
影响因子：
3.3
通讯作者：
Hu Zhaoyang
中科院分区：
文献类型：
--
作者：
Yang Shuai;Abbott W. Geoffrey;Gao Wei Dong;Liu Jin;Luo Chaozhi;Hu Zhaoyang
已有令人信服的证据表明，远程缺血处理可以使心肌对随后更严重的持续缺血发作具有抵抗力。与其他器官相比，短暂性肝脏缺血预适应的影响知之甚少。我们提出了远程肝脏调理引起的心脏保护作用的存在。将雄性SD大鼠分为假手术对照组(不作进一步肝脏干预)和远距离肝脏缺血预适应组。在肝脏缺血处理中，在-(肝脏预处理)、心肌缺血后(肝脏后处理)或两者结合(肝脏预处理+肝脏后处理)前进行3个周期的5min肝脏缺血-再灌注刺激。结扎大鼠冠状动脉前降支45min，然后再灌流3h。在整个实验过程中测量了心电图和血流动力学。在再灌流结束时再闭塞冠状动脉，以确定梗塞面积。采血检测血清乳酸脱氢酶和肌酸激酶-MB活性。取心脏组织进行细胞凋亡检测和Western blotting。我们的数据表明，肝脏缺血预适应、后处理或两者的组合提供了强大的心脏保护，表现为减少梗塞面积和心脏组织损伤，恢复心功能，并抑制缺血-再灌注后的细胞凋亡。此外，肝脏缺血预适应增加了心脏(而非肝脏)糖原合成酶β-3(β)的磷酸化。因此，抑制葛兰素史克-3β类似于肝脏调理的心脏保护作用。这些结果表明，远距离肝脏缺血预适应通过依赖GSK-3β的细胞生存信号通路保护心脏免受缺血和再灌注损伤。然而，目前尚不清楚肝脏等内脏器官的缺血适应能否产生心脏保护作用。肝脏是人体最大的代谢器官。这是首次在大鼠心肌I/R损伤模型上显示远程肝脏缺血预适应的心脏保护作用的研究。我们还首次证明了这些保护特性与糖原合成酶激酶-3β依赖的细胞生存信号通路有关。
Remote ischemic conditioning has been convincingly shown to render the myocardium resistant to a subsequent more severe sustained episode of ischemia. Compared with other organs, little is known regarding the effect of transient liver ischemic conditioning. We proposed the existence of cardioprotection induced by remote liver conditioning. Male Sprague-Dawley rats were divided into sham-operated control (no further hepatic intervention) and remote liver ischemic conditioning groups. For liver ischemic conditioning, three cycles of 5 min of liver ischemia-reperfusion stimuli were conducted before-(liver preconditioning), post-myocardial ischemia (liver postconditioning), or in combination of both (liver preconditioning + liver postconditioning). Rats were exposed to 45 min of left anterior descending coronary artery occlusion, followed by 3 h of reperfusion thereafter. ECG and hemodynamics were measured throughout the experiment. The coronary artery was reoccluded at the end of reperfusion for infarct size determination. Blood samples were taken for serum lactate dehydrogenase and creatine kinase-MB test. Heart tissues were taken for apoptosis measurements and Western blotting. Our data demonstrate that liver ischemic preconditioning, postconditioning, or a combination of both, offered strong cardioprotection, as evidenced by reduction in infarct size and cardiac tissue damage, recovery of cardiac function, and inhibition of apoptosis after ischemia-reperfusion. Moreover, liver ischemic conditioning increased cardiac (not hepatic) glycogen synthase kinase-3β (GSK-3β) phosphorylation. Accordingly, inhibition of GSK-3β mimicked the cardioprotective action of liver conditioning. These results demonstrate that remote liver ischemic conditioning protected the heart against ischemia and reperfusion injury via GSK-3β-dependent cell-survival signaling pathway.NEW & NOTEWORTHYRemote ischemic conditioning protects hearts against ischemia and reperfusion (I/R) injury. However, it is unclear whether ischemic conditioning of visceral organs such as the liver, the largest metabolic organ in the body, can produce cardioprotection. This is the first study to show the cardioprotective effect of remote liver ischemic conditioning in a rat model of myocardial I/R injury. We also, for the first time, demonstrated these protective properties are associated with glycogen synthase kinase-3β-dependent cell-survival signaling pathway.