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Involvement of nuclear factor-κB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy
被引:319
作者:
Hirotani, S
Otsu, K
Nishida, K
Higuchi, Y
Morita, T
Nakayama, H
Yamaguchi, O
Mano, T
Matsumura, Y
Ueno, H
Tada, M
Hori, M
机构:
[1] Osaka Univ, Grad Sch Med, Dept Pathophysiol, Suita, Osaka 5650871, Japan
[2] Osaka Univ, Grad Sch Med, Dept Internal Med & Therapeut, Suita, Osaka, Japan
[3] Osaka Univ, Grad Sch Med, Dept Med Informat Sci, Suita, Osaka, Japan
[4] Univ Occupat & Environm Hlth, Sch Med, Dept Biochem & Mol Pathophysiol, Kitakyushu, Fukuoka, Japan
关键词:
hypertrophy;
myocytes;
signal transduction;
free radicals;
D O I:
10.1161/hc0402.102863
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
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.
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页码:509 / 515
页数:7
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