An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia

作     者：Mackay, K Mochly-Rosen, D 

作者机构：Stanford Univ Sch Med Dept Mol Pharmacol Stanford CA 94305 USA 

出 版 物：《JOURNAL OF BIOLOGICAL CHEMISTRY》 (生物化学杂志)

年 卷 期：1999年第274卷第10期

页      面：6272-6279页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：NHLBI NIH HHS [HL-52141] Funding Source: Medline 

主　　题：钙-钙调素依赖性蛋白激酶类/拮抗剂和抑制剂 钙-钙调素依赖性蛋白激酶类/代谢 酶抑制剂/药理学 酶抑制剂/治疗应用 心室/酶学 心室/病理学 咪唑类/药理学 咪唑类/治疗应用 丝裂原激活蛋白激酶类 心肌缺血/酶学 心肌缺血/预防和控制 磷酰化 吡啶类/药理学 吡啶类/治疗应用 大鼠 Sprague-Dawley p38丝裂原活化蛋白激酶类 动物 大鼠 

摘      要：Cellular ischemia results in activation of a number of kinases, including p38 mitogen-activated protein kinase (MAPK);however, it is not yet clear whether p38 MAPK activation plays a role in cellular damage or is part of a protective response against ischemia, We have developed a model to study ischemia in cultured neonatal rat cardiac myocytes. In this model, two distinct phases of p38 MAPK activation were observed during ischemia. The first phase began within 10 min and lasted less than 1 h, and the second began after 2 h and lasted throughout the ischemic period. Similar to previous studies using in vivo models, the nonspecific activator of p38 MAPK and c-Jun NH2-terminal kinase, anisomycin, protected cardiac myocytes from ischemic injury, decreasing the release of cytosolic lactate dehydrogenase by approximately 25%. We demonstrated, however, that a selective inhibitor of p38 MAPK, SB 203580, also protected cardiac myocytes against extended ischemia in a dose-dependent manner. The protective effect was seen even when the inhibitor was present during only the second, sustained phase of p38 MAPK activation. We found that ischemia induced apoptosis in neonatal rat cardiac myocytes and that SE 203580 reduced activation of caspase-3, a key event in apoptosis. These results suggest that p38 MAPK induces apoptosis during ischemia in cardiac myocytes and that selective inhibition of p58 MAPK could be developed as a potential therapy for ischemic heart disease.