Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy
Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy
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DOI：
10.1172/jci3512
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发表时间：
1998-10-01
影响因子：
15.9
通讯作者：
Force, T
中科院分区：
文献类型：
--
作者：
Choukroun, G;Hajjar, R;Force, T
控制心肌细胞肥大反应的信号转导途径尚未明确。通过过表达途径各种成分的激活突变体来组成性激活丝裂原激活蛋白 (MAP) 激酶的应激激活蛋白激酶 (SAPK) 家族或另一种应激反应 MAP 激酶 p38，足以诱导心肌细胞肥大反应，但尚不清楚这些途径在对生理相关肥大刺激的反应中发挥什么作用。为了确定 SAPK 在肥大反应中的作用，我们使用腺病毒介导的 SAPK/ERK 激酶-1 (KR) [SEK-1(KR)] 基因转移（SEK-1 的显性抑制突变体，SAPK 的直接上游激活剂）来阻断 SAPK 通路中对强效肥大剂内皮素-1 (ET-1) 的信号传递。 SEK-1(KR) 完全抑制 ET-1 诱导的 SAPK 激活，而不影响与肥大反应有关的其他 MAP 激酶、p38 和细胞外信号调节蛋白激酶 (ERK)-1/ERK-2 的激活，SEK-1(KR) 的表达显着抑制 ET-1 诱导的蛋白质合成增加。相比之下，阻断 ERK 激活的 MAPK/ERK 激酶抑制剂 PD98059 和 p38 抑制剂 SB203580 对 ET-1 诱导的蛋白质合成没有影响。 ET-1 还诱导心房钠尿因子 mRNA 表达以及具有高度组织化的肌节的细胞百分比显着增加，这些反应也被 SEK-1(KR) 的表达所阻断。总之，抑制 SAPK 途径的激活消除了对 ET-1 的肥大反应。这些数据首次证明 SAPK 对于激动剂诱导的心肌细胞肥大的发展是必需的，并表明，响应ET-1，它们转导控制肥大反应的关键信号。
The signal transduction pathways governing the hypertrophic response of cardiomyocytes are not well defined. Constitutive activation of the stress-activated protein kinase (SAPK) family of mitogen-activated protein (MAP) kinases or another stress-response MAP kinase, p38, by overexpression of activated mutants of various components of the pathways is sufficient to induce a hypertrophic response in cardiomyocytes, but it is not clear what role these pathways play in the response to physiologically relevant hypertrophic stimuli. To determine the role of the SAPKs in the hypertrophic response, we used adenovirus-mediated gene transfer of SAPK/ERK kinase-1 (KR) [SEK-1(KR)], a dominant inhibitory mutant of SEK-1, the immediate upstream activator of the SAPKs, to block signal transmission down the SAPK pathway in response to the potent hypertrophic agent, endothelin-1 (ET-1). SEK-1(KR) completely inhibited ET-1-induced SAPK activation without affecting activation of the other MAP kinases implicated in the hypertrophic response, p38 and extracellular signal-regulated protein kinases (ERK)-1/ERK-2, Expression of SEK-1(KR) markedly inhibited the ET-1-induced increase in protein synthesis. In contrast, the MAPK/ERK kinase inhibitor, PD98059, which blocks ERK activation, and the p38 inhibitor, SB203580, had no effect on ET-1-induced protein synthesis. ET-1 also induced a significant increase in atrial natriuretic factor mRNA expression as well as in the percentage of cells with highly organized sarcomeres, responses which were also blocked by expression of SEK-1(KR), In summary, inhibiting activation of the SAPK pathway abrogated the hypertrophic response to ET-1, These data are the first demonstration that the SAPKs are necessary for the development of agonist-induced cardiomyocyte hypertrophy, and suggest that in response to ET-1, they transduce critical signals governing the hypertrophic response.