12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes

Motohiro Nishida, Shihori Tanabe, Yoshiko Maruyama, Supachoke Mangmool, Kyoji Urayama, Yuichi Nagamatsu, Shuichi Takagahara, Justin H. Turner, Tohru Kozasa, Hiroyuki Kobayashi, Yoji Sato, Toru Kawanishi, Ryuji Inoue, Taku Nagao, Hitoshi Kurose

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118 Citations (Scopus)


In the present study, we examined signal transduction mechanism of reactive oxygen species (ROS) production and the role of ROS in angiotensin II-induced activation of mitogen-activated protein kinases (MAPKs) in rat neonatal cardiomyocytes. Among three MAPKs, c-Jun NH2-terminal kinase (JNK) and p38 MAPK required ROS production for activation, as an NADPH oxidase inhibitor, diphenyleneiodonium, inhibited the activation. The angiotensin II-induced activation of JNK and p38 MAPK was also inhibited by the expression of the Gα12/13-specific regulator of G protein signaling (RGS) domain, a specific inhibitor of Gα12/13, but not by an RGS domain specific for Gαq. Constitutively active Gα12- or Gα13-induced activation of JNK and p38 MAPK, but not extracellular signal-regulated kinase (ERK), was inhibited by diphenyleneiodonium. Angiotensin II receptor stimulation rapidly activated Gα13, which was completely inhibited by the Gα12/13-specific RGS domain. Furthermore, the Gα12/13-specific but not the Gαq-specific RGS domain inhibited angiotensin II-induced ROS production. Dominant negative Rac inhibited angiotensin II-stimulated ROS production, JNK activation, and p38 MAPK activation but did not affect ERK activation. Rac activation was mediated by Rho and Rho kinase, because Rac activation was inhibited by C3 toxin and a Rho kinase inhibitor, Y27632. Furthermore, angiotensin II-induced Rho activation was inhibited by Gα12/13-specific RGS domain but not dominant negative Rac. An inhibitor of epidermal growth factor receptor kinase AG1478 did not affect angiotensin II-induced JNK activation cascade. These results suggest that Gα12/13-mediated ROS production through Rho and Rac is essential for JNK and p38 MAPK activation.

Original languageEnglish
Pages (from-to)18434-18441
Number of pages8
JournalJournal of Biological Chemistry
Issue number18
Publication statusPublished - May 6 2005

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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