The small GTP-binding protein rac1 induces cardiac myocyte hypertrophy through the activation of apoptosis signal-regulating kinase 1 and nuclear Factor-κB
The small GTP-binding protein rac1 induces cardiac myocyte hypertrophy through the activation of apoptosis signal-regulating kinase 1 and nuclear Factor-κB
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DOI：
10.1074/jbc.m213203200
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发表时间：
2003-06-06
影响因子：
4.8
通讯作者：
Hori, M
中科院分区：
文献类型：
--
作者：
Higuchi, Y;Otsu, K;Hori, M
小鸟嘌呤核苷酸结合蛋白Rac 1已成为参与心肌细胞肥大的重要分子。最近，我们报道了凋亡信号调节激酶（ASK）1和转录因子，核因子-κ B（NF-κ B），作为新的信号中间体在心肌细胞肥大。本研究的目的是阐明Rac 1在ASK 1-NF-κ B信号通路中的作用。用表达组成型活性形式的Rac 1（Rac V12）的腺病毒感染分离的新生心肌细胞，增强了κ B依赖性报告基因构建体的表达，并诱导了IkappaB α的降解。IkappaB α的抗降解突变体的表达抑制了RacV 12诱导的肥大反应，包括蛋白质合成和心钠素产生的增加以及肌节组织的增强。免疫复合物激酶试验表明RacV 12的表达激活了ASK 1。ASK 1的显性负突变体的表达消除了RacV 12诱导的NF-κ B活化以及生化和形态学肥大反应，而Rac 1的显性负形式的表达减弱了苯肾上腺素诱导的ASK 1和NF-κ B活化以及心肌细胞肥大。这些发现表明Rac 1通过ASK 1和NF-κ B介导诱导心肌细胞肥大。
The small guanine nucleotide-binding protein Rac1 has emerged as an important molecule involved in cardiac myocyte hypertrophy. Recently, we reported on apoptosis signal-regulating kinase (ASK) 1 and a transcriptional factor, nuclear factor-kappaB (NF-kappaB), as novel signaling intermediates in cardiac myocyte hypertrophy. The aim of the study presented here was to clarify the role of Rac1 in the ASK1-NF-kappaB signaling pathway. Infection of isolated neonatal cardiac myocytes with an adenovirus expressing a constitutively active form of Rac1 (RacV12) enhanced the expression of a kappaB-dependent reporter gene construct and induced the degradation of IkappaBalpha. Expression of a degradation-resistant mutant of IkappaBalpha inhibited the RacV12-induced hypertrophic responses, including increases in protein synthesis and atrial natriuretic factor production and the enhancement of sarcomeric organization. An immune complex kinase assay indicated that the expression of RacV12 activated ASK1. Expression of a dominant negative mutant of ASK1 eliminated the RacV12-induced NF-kappaB activation and the biochemical and morphological hypertrophic responses, whereas expression of a dominant negative form of Rac1 attenuated phenylephrine-induced activation of ASK1 and NF-kappaB and cardiac myocyte hypertrophy. These findings suggest that Rac1 induces cardiac myocyte hypertrophy mediated through ASK1 and NF-kappaB.