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
Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Biochem Biophys Res Commun. 2005 Feb 4;327(1):136-42. doi: 10.1016/j.bbrc.2004.12.002.
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.
钙调蛋白依赖蛋白激酶（CaMK）是肥厚信号通路中Ca2+的重要下游靶点。我们先前表明，凋亡信号调节激酶1（ASK1）或核因子κB（NF-κB）的激活足以导致心肌细胞肥大。用表达CaMKIIdelta3的腺病毒载体（AdCaMKIIdelta3）感染分离的新生心肌细胞可诱导ASK1激活，而CaMKII抑制剂KN93可抑制去甲肾上腺素诱导的ASK1激活。CaMKIIdelta3的过表达诱导了体外心肌细胞肥大的特征性表现。用表达ASK1显性负性突变体的腺病毒载体（AdASK(KM)）感染心肌细胞可抑制CaMKIIdelta3诱导的肥大反应。CaMKIIdelta3的过表达增加了κB依赖的启动子/荧光素酶活性并诱导IκBα降解。AdCaMKIIdelta3与AdASK(KM)共感染以及与KN93预孵育分别减弱了CaMKIIdelta3和去甲肾上腺素诱导的NF-κB激活。IκBα降解抗性突变体的表达抑制了CaMKIIdelta3诱导的肥大反应。这些结果表明，CaMKIIdelta3通过ASK1-NF-κB信号转导途径诱导心肌细胞肥大。
