Involvement of nuclear factor-κB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy
Involvement of nuclear factor-κB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy
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DOI：
10.1161/hc0402.102863
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发表时间：
2002-01-29
期刊：
影响因子：
37.8
通讯作者：
Hori, M
中科院分区：
文献类型：
--
作者：
Hirotani, S;Otsu, K;Hori, M
近年来，活性氧（reactive oxygen species， ROS）已成为心肌肥厚的重要分子。然而，ros依赖的信号转导机制仍有待阐明。在这项研究中，我们检测了ros敏感转录因子NF-kappaB和丝裂原激活蛋白激酶激酶激酶凋亡信号调节激酶I （ASK1）在g蛋白偶联受体（GPCR）激动剂（血管紧张素11、内皮素1、苯肾上腺素）诱导的离体大鼠新生心肌细胞心肌肥大中的作用。方法与结果：采用ros敏感的荧光染料，我们观察到加入GPCR激动剂后荧光信号增加。GPCR激动剂诱导NF-kappaB活化。抗氧化剂如n -乙酰半胱氨酸、n -巯基丙酰甘氨酸和维生素E可减弱NF-kappaB的活化。用表达IkappaBalpha降解抗性突变体的腺病毒感染心肌细胞可抑制肥厚反应。GPCR激动剂以剂量依赖的方式快速瞬时激活ASK1。表达显性阴性ASK1的腺病毒感染可减弱GPCR激动剂诱导的NF-kappaB激活和心脏肥厚。ASK1组成型活性突变体的过表达导致NF-kappaB激活和心脏肥厚。活化的ask1诱导的肥大通过抑制NF-kappaB激活而被消除。结论-这些数据表明，GPCR激动剂诱导的心肌肥厚是通过产生ROS激活NF-kappaB介导的。ASK1参与GPCR激动剂诱导的NF-kappaB活化和导致的肥大。
Background-Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-kappaB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase I (ASK1), in G-protein-coupled receptor (GPCR) agonist (angiotensin 11, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes.Methods and Results-Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-kappaB activation. Antioxidants such as N-acetyl cysteine, N-mercaptopropionyl glycine, and vitamin E attenuated the NF-kappaB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant Of IkappaBalpha led to suppression of the hypertrophic responses. The GPCR agonists rapidly and transiently activated ASK1 in a dose-dependent manner. Infection of an adenovirus expressing a dominant-negative ASK1 attenuated the GPCR agonist-induced NF-kappaB activation and cardiac hypertrophy. Overexpression of a constitutively active mutant of ASK1 led to NF-kappaB activation and cardiac hypertrophy. Activated ASK1-induced hypertrophy was abolished by inhibition of NF-kappaB activation.Conclusions-These data indicate that GPCR agonist-induced cardiac hypertrophy is mediated through NF-kappaB activation via the generation of ROS. ASK1 is involved in GPCR agonist-induced NF-kappaB activation and resulting hypertrophy.