ERK-MAPK Signaling Opposes Rho-Kinase to Reduce Cardiomyocyte Apoptosis in Heart Ischemic Preconditioning
ERK-MAPK Signaling Opposes Rho-Kinase to Reduce Cardiomyocyte Apoptosis in Heart Ischemic Preconditioning
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DOI：
10.2119/molmed.2009.00121
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发表时间：
2010-07-01
影响因子：
5.7
通讯作者：
Ji, Xiao-Ping
中科院分区：
文献类型：
--
作者：
Juan-Zhang;Bian, Hong-Jun;Ji, Xiao-Ping
我们和其他人已经报道，Rho-Kinase在心脏缺血/再灌注(I/R)损伤的发病机制中发挥重要作用。研究还表明，在缺血预适应(IPC)中，Rho-Kinase的激活被逆转。然而，Rho-Kinase在I/R中增加和在IPC中被逆转的机制还不完全清楚。在雌性Wistar大鼠，结扎冠状动脉左前降支(LAD)30min，松解结扎180min，建立I/R模型。IPC大鼠在I/R前接受IPC(LAD结扎5分钟和再流5分钟两个循环)，IPC导致细胞外信号调节激酶(ERK)(1/2)活性显著增加，Rho-Kinase活性和心肌细胞凋亡减少(P<；0.05与I/R相比)。给予ERK丝裂原活化蛋白激酶(MAPK)抑制剂PD98059可增加心肌细胞凋亡率、Caspase-3活性和心肌梗死范围(P<；0.05与IPC相比)。Western-blotting分析显示，给予PD98059可增加Rho-Kinase活性。Rho-Kinase抑制剂法舒地尔可逆转PD98059诱导的IPC细胞凋亡。此外，ROCK1(Rho-kinase1)可能是IPC中与ERK-MAPK信号相反的主要Rho-kinase1。这些结果表明，在IPC中需要ERK-MAPK信号来对抗在体心肌细胞凋亡中的Rho-Kinase活性。(C)2010年范斯坦医学研究所，www.festeinInstitute te.org
We and others have reported that Rho-kinase plays an important role in the pathogenesis of heart ischemia/reperfusion (I/R) injury. Studies have also demonstrated that the activation of Rho-kinase is reversed in ischemic preconditioning (IPC). However, the mechanisms by which Rho-kinase is increased in I/R and reversed in IPC are not thoroughly understood. In female Wistar rats, we created I/R by ligating the left anterior-descending branch of the coronary artery (LAD) for 30 min and releasing the ligature for 180 min. IPC rats underwent IPC (two cycles of 5-min ligation of the LAD and 5-min reflow) before I/R. IPC caused a significant increase in extracellular signal-regulated kinase (ERK)(1/2) activity and reduced Rho-kinase activity and cardiomyocyte apoptosis (P < 0.05 versus I/R). Administration of PD98059, an inhibitor of ERK-mitogen-activated protein kinase (MAPK), increased cardiomyocyte apoptosis, Caspase-3 activity and myocardial infarction size (P < 0.05 versus IPC). Western-blot analysis showed that administration of PD98059 increased Rho-kinase activity. Treatment with fasudil, an inhibitor of Rho-kinase, reversed cell apoptosis caused by treatment with PD98059 in IPC. In addition, ROCK1 (Rho-kinase 1) may be the major Rho-kinase isoform that is opposed by ERK-MAPK signaling in IPC. These results indicate that ERK-MAPK signaling is required in IPC to oppose Rho-kinase activity in cardiomyocyte apoptosis in vivo. (C) 2010 The Feinstein Institute for Medical Research, www.feinsteininstitute.org