CaMKII activates ASK1 and NF-kappaB to induce cardiomyocyte hypertrophy |
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Authors: | Kashiwase Kazunori Higuchi Yoshiharu Hirotani Shinichi Yamaguchi Osamu Hikoso Shungo Takeda Toshihiro Watanabe Tetsuya Taniike Masayuki Nakai Atsuko Tsujimoto Ikuko Matsumura Yasushi Ueno Hikaru Nishida Kazuhiko Hori Masatsugu Otsu Kinya |
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Affiliation: | Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. |
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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. |
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Keywords: | Cardiomyocyte hypertrophy Ca2+ CaMKII CaM kinase II ASK1 NF-κB GPCR agonist |
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