Delayed adenosine A1 receptor preconditioning in rat myocardium is MAPK dependent but iNOS independent
Delayed adenosine A1 receptor preconditioning in rat myocardium is MAPK dependent but iNOS independent
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DOI：
10.1152/ajpheart.01008.2004
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发表时间：
2005-08-01
影响因子：
4.8
通讯作者：
Mentzer, RM
中科院分区：
文献类型：
--
作者：
Lasley, RD;Keith, BJ;Mentzer, RM
腺苷A（1）受体延迟预处理（PC）对心肌梗死的作用已被广泛报道，但对介导这一现象的信号转导机制的研究还很有限。此外，关于诱导型一氧化氮合酶（iNOS）在介导A（1）晚期PC中的作用有多个相互矛盾的报道。本研究的目的是确定p38和细胞外信号调节激酶（ERK）丝裂原活化蛋白激酶（MAPK）在体内延迟A（1）受体PC中的作用，以及这种在心肌细胞水平的保护作用是否是由于iNOS的上调。在开胸麻醉的大鼠中，用溶剂或腺苷A（1）激动剂2-氯-N-6-环戊基腺苷（CCPA; 100 μ g/kg ip）处理24小时后，测量心肌梗死面积。接受CCPA的其他大鼠用p38抑制剂SB-203580（1 mg/kg ip）或MAPK/ERK激酶（MEK）抑制剂PD-098059（0.5 mg/kg ip）预处理。CCPA给药后24 h，缺血前10 min给予iNOS抑制剂1400 W。CCPA治疗使梗死面积从48 +/-2%降至28 +/- 2%，SB-203580和PD-098059均能阻断该效应，但1400 W不能。注射CCPA后24小时分离的心室肌细胞在H2 O2暴露期间表现出显着降低的氧化应激与注射溶剂的动物的心肌细胞相比，这种效果并没有被阻断的iNOS抑制剂1400 W。Western印迹分析显示，CCPA治疗后6或24小时，整个心脏和心肌细胞蛋白样品中没有表达的诱导型一氧化氮合酶。这些结果提示腺苷A1受体延迟大鼠PC是由MAPK依赖性机制介导的，但这种现象与iNOS的早期或晚期表达无关。
Adenosine A(1) receptor delayed preconditioning (PC) against myocardial infarction has been well described; however, there have been limited investigations of the signaling mechanisms that mediate this phenomenon. In addition, there are multiple conflicting reports on the role of inducible nitric oxide synthase (iNOS) in mediating A(1) late-phase PC. The purpose of this study was to determine the roles of the p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs) in in vivo delayed A(1) receptor PC and whether this protection at the myocyte level is due to upregulation of iNOS. Myocardial infarct size was measured in open-chest anesthetized rats 24 h after treatment with vehicle or the adenosine A(1) agonist 2-chloro-N-6-cyclopentyladenosine (CCPA; 100 mu g/kg ip). Additional rats receiving CCPA were pretreated with the p38 inhibitor SB-203580 (1 mg/kg ip) or the MAPK/ERK kinase (MEK) inhibitor PD-098059 (0.5 mg/kg ip). At 24 h after CCPA administration, a group of animals was given the iNOS inhibitor 1400W 10 min before ischemia. Treatment with CCPA reduced infarct size from 48 +/- 2 to 28 +/- 2% of the area at risk, an effect that was blocked by both SB-203580 and PD-098059 but not 1400W. Ventricular myocytes isolated 24 h after CCPA injection exhibited significantly reduced oxidative stress during H2O2 exposure compared with myocytes from vehicle-injected animals, and this effect was not blocked by the iNOS inhibitor 1400W. Western blot analysis of whole heart and cardiac myocyte protein samples revealed no expression of iNOS 6 or 24 h after CCPA treatment. These results indicate that adenosine A(1) receptor delayed PC in rats is mediated by MAPK-dependent mechanisms, but this phenomenon is not associated with the early or late expression of iNOS.