Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy
Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy
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DOI：
10.1074/jbc.m007037200
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发表时间：
2000-12-01
影响因子：
4.8
通讯作者：
Ohlstein, EH
中科院分区：
文献类型：
--
作者：
Yue, TL;Gu, JL;Ohlstein, EH
细胞外信号调节激酶通路在心肌细胞中被肥大刺激激活，然而，细胞外信号调节激酶是否在心肌肥厚的所有主要成分中起重要作用或是否参与肥厚的所有主要成分仍存在争议。我们使用选择性细胞外信号调节激酶抑制剂U0126和选择性Raf抑制剂SB-386023在两个不同的水平阻断细胞外信号调节激酶信号通路，并通过腺病毒介导的显性负性Raf基因转导，研究了细胞外信号调节激酶信号在肥大激动剂内皮素-L(ET-1)和苯肾上腺素(PE)反应中的作用。U0126和SB-386023可阻断ET I和PE诱导的心肌细胞ERK的激活，但不能阻断p38和JNK的激活。两个化合物均抑制ET-1和PE诱导的蛋白质合成，增加细胞大小、肌节重组和P-肌球蛋白重链的表达，IC_1为1~2微米。此外，两种抑制剂均显著降低ET-1和PE诱导的心钠素的表达。与腺病毒表达绿色荧光蛋白的细胞相比，转染显性负性Raf的心肌细胞中，ET-1和PE诱导的细胞大小增加、肌节重组和心钠素的产生显著减弱。综上所述，我们的数据有力地支持了ERK信号通路在ET-1和PE诱导的心肌细胞肥大中起重要作用的观点。
The extracellular signal-regulated kinase (ERK) pathway is activated by hypertrophic stimuli in cardiomyocytes, However, whether ERK plays an essential role or is implicated in all major components of cardiac hypertrophy remains controversial, Using a selective MEK inhibitor, U0126, and a selective Raf inhibitor, SB-386023, to block the ERK signaling pathway at two different levels and adenovirus-mediated transfection of dominant-negative Raf, we studied the role of ERK signaling in response of cultured rat cardiomyocytes to hypertrophic agonists, endothelin-l (ET-1), and phenylephrine (PE). U0126 and SB-386023 blocked ET I and PE-induced ERK but not p38 and JNK activation in cardiomyocytes. Both compounds inhibited ET-1 and PE-induced protein synthesis and increased cell size, sarcomeric reorganization, and expression of P-myosin heavy chain in myocytes with IC,, values of 1-2 muM. Furthermore, both inhibitors significantly reduced ET-1- and PE-induced expression of atrial natriuretic factor. In cardiomyocytes transfected with a dominant-negative Raf, ET-1- and PE-induced increase in cell size, sarcomeric reorganization, and atrial natriuretic factor production were remarkably attenuated compared with the cells infected with an adenovirus-expressing green fluorescence protein. Taken together, our data strongly support the notion that the ERK signal pathway plays an essential role in ET-1- and PE-induced cardiomyocyte hypertrophy.