title: Involvement of nuclear factor-kappaB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy.
abstract: 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 1 (ASK1), in G-protein-coupled receptor (GPCR) agonist (angiotensin II, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes.
  
  
  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.
authors.affiliation: Department of Pathophysiology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirotani
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishida
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mano
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ueno
authors.forename: Michihiko
authors.initials: M
authors.lastname: Tada
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D048429:Cell Size; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000235:genetics; D007700:Kinetics; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D016328:NF-kappa B / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists; D012518:Sarcomeres / Q000648:ultrastructure
chemical_list: D019332:Endothelin-1; D020672:I-kappa B Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D000804:Angiotensin II; D010656:Phenylephrine; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D020962:Heterotrimeric GTP-Binding Proteins