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CaMKII activates ASK1 and NF-kappaB to induce cardiomyocyte hypertrophy.

Abstract
Ca2+/calmodulin-dependent protein kinase (CaMK) is an important downstream target of Ca2+ in the hypertrophic signaling pathways. We previously showed that the activation of apoptosis signal-regulating kinase 1 (ASK1) or NF-kappaB is sufficient for cardiomyocyte hypertrophy. Infection of isolated neonatal cardiomyocytes with an adenoviral vector expressing CaMKIIdelta3 (AdCaMKIIdelta3) induced the activation of ASK1, while KN93, an inhibitor of CaMKII, inhibited phenylephrine-induced ASK1 activation. Overexpression of CaMKIIdelta3 induced characteristic features of in vitro cardiomyocyte hypertrophy. Infection of cardiomyocytes with an adenoviral vector expressing a dominant negative mutant of ASK1 (AdASK(KM)) inhibited the CaMKIIdelta3-induced hypertrophic responses. Overexpression of CaMKIIdelta3 increased the kappaB-dependent promoter/luciferase activity and induced IkappaBalpha degradation. Coinfection with AdCaMKIIdelta3 and AdASK(KM), and pre-incubation with KN93 attenuated CaMKIIdelta3- and phenylephrine-induced NF-kappaB activation, respectively. Expression of a degradation resistant mutant of IkappaBalpha inhibited CaMKIIdelta3-induced hypertrophic responses. These results indicate that CaMKIIdelta3 induces cardiomyocyte hypertrophy mediated through ASK1-NF-kappaB signal transduction pathway.
AuthorsKazunori Kashiwase, Yoshiharu Higuchi, Shinichi Hirotani, Osamu Yamaguchi, Shungo Hikoso, Toshihiro Takeda, Tetsuya Watanabe, Masayuki Taniike, Atsuko Nakai, Ikuko Tsujimoto, Yasushi Matsumura, Hikaru Ueno, Kazuhiko Nishida, Masatsugu Hori, Kinya Otsu
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 327 Issue 1 Pg. 136-42 (Feb 04 2005) ISSN: 0006-291X [Print] United States
PMID15629441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-kappa B
  • Hydrogen Peroxide
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Calcium
Topics
  • Animals
  • Calcium (pharmacology)
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases (genetics, metabolism)
  • Cardiomegaly (metabolism, pathology)
  • Cells, Cultured
  • Enzyme Activation (drug effects)
  • Gene Expression Regulation
  • Hydrogen Peroxide (pharmacology)
  • MAP Kinase Kinase Kinase 5 (genetics, metabolism)
  • Myocytes, Cardiac (metabolism, pathology)
  • NF-kappa B (metabolism)
  • Rats
  • Rats, Wistar
  • Signal Transduction

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