Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: Comparison with acute mechanical stretch
Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: Comparison with acute mechanical stretch
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DOI：
10.1006/jmcc.2001.1427
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发表时间：
2001-09-01
影响因子：
5
通讯作者：
Walsh, RA
中科院分区：
文献类型：
--
作者：
Samarel, AM;Takeishi, Y;Walsh, RA
有研究认为，丝裂原活化蛋白激酶家族成员及其下游效应物的激活在细胞存活、缺血预处理、心肌肥厚和心力衰竭的发病机制中起关键作用。本研究探讨了Src激酶和多种MAP激酶在代偿性压力过载肥厚向失代偿性充血性心力衰竭转变过程中的反应。细胞外信号调节蛋白激酶（ERK） 1/2、p3g和Src被慢性压力过载激活，它们的活性在主动脉束带后持续8周。相比之下，尽管p90核糖体S6激酶（90RSK）和大MAP激酶1 （BMK1）在代偿性肥厚中被激活，但它们的活性在心力衰竭时显著降低。主动脉束带后C-Jun NH2末端激酶（JNK）活性未见变化。这些数据表明，MAP激酶家族成员的差异激活可能有助于从代偿性肥厚过渡到失代偿性肥厚。我们还研究了机械拉伸对正常和肥大心脏中这些激酶激活的急性影响。在孤立的冠状动脉灌注心脏。左心室充气球囊，使舒张末压降至25mmhg，持续10-20min。在正常的豚鼠心脏中。拉伸激活ERK1/2， p90RSK, p38, Src。和BMK1，而不是JNK。然而在肥厚的心脏中。急性机械拉伸未观察到这些激酶的进一步活化。在正常心脏中，机械拉伸诱导的ERK1/2和p38激酶的激活被蛋白激酶C抑制剂chelerythrine显著减弱。研究表明，ERK1/2、p90RSK、p38、Src和BMK1可被慢性压力过载和急性机械拉伸激活。这些数据表明Src。BMK1和p90RSK是导致心脏肥厚的新信号转导途径。此外，p90RSK和BMK1在充血性心力衰竭心脏中的差异抑制提示这两种激酶在慢性压力过载下维持心功能的特殊作用。(C) 2001学术出版社。
Activation of members of the mitogen-activated protein (MAP) kinase family and their downstream effectors has been proposed to play a key role in the pathogenesis of cell survival, ischaemic preconditioning, cardiac hypertrophy and heart failure. This study investigated the responses of Src kinase and multiple MAP kinases during the transition from compensated pressure-overload hypertrophy to decompensated congestive heart failure. Extracellular signal-regulated protein kinase (ERK) 1/2, p3g, and Src were activated by chronic pressure-overload and their activity was sustained for 8 weeks after aortic banding. In contrast, while p90 ribosomal S6 kinase (90RSK) and big MAP kinase 1 (BMK1) were activated in compensated hypertrophy, their activities were significantly decreased in hearts with heart failure. No changes were found in C-Jun NH2 terminal kinase (JNK) activity after aortic banding. These data suggest that differential activation of MAP kinase family members may contribute to the transition from compensated to decompensated hypertrophy. We also examined acute effects of mechanical stretch on the activation of these kinases in normal and hypertrophied hearts. In the isolated coronary-perfused heart. a balloon in the left ventricle was inflated to achieve minimum end-diastolic pressure of 25 mmHg for 10-20min. In normal guinea pig hearts. stretch activated ERK1/2, p90RSK, p38, Src. and BMK1 but not JNK. However in hypertrophied hearts. further activation of these kinases was not observed by acute mechanical stretch. Mechanical stretch-induced activation of ERK1/2 and p38 kinase in normal hearts was attenuated significantly by a protein kinase C inhibitor, chelerythrine. We demonstrate that ERK1/2, p90RSK, p38, Src, and BMK1 are activated by chronic pressure-overload and by acute mechanical stretch. These data suggest that Src. BMK1 and p90RSK play a role as novel signal transduction pathways leading to cardiac hypertrophy. In addition, the differential inhibition of p90RSK and BMK1 in hearts with congestive heart failure suggests the specific role of these two kinases to maintain cardiac function under chronic pressure-overload. (C) 2001 Academic Press.