title: G alpha 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.
abstract: 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 NH(2)-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 Galpha(12/13)-specific regulator of G protein signaling (RGS) domain, a specific inhibitor of Galpha(12/13), but not by an RGS domain specific for Galpha(q). Constitutively active Galpha(12)- or Galpha(13)-induced activation of JNK and p38 MAPK, but not extracellular signal-regulated kinase (ERK), was inhibited by diphenyleneiodonium. Angiotensin II receptor stimulation rapidly activated Galpha(13), which was completely inhibited by the Galpha(12/13)-specific RGS domain. Furthermore, the Galpha(12/13)-specific but not the Galpha(q)-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 Galpha(12/13)-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 Galpha(12/13)-mediated ROS production through Rho and Rac is essential for JNK and p38 MAPK activation.
authors.affiliation: Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.forename: Shihori
authors.initials: S
authors.lastname: Tanabe
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Supachoke
authors.initials: S
authors.lastname: Mangmool
authors.forename: Kyoji
authors.initials: K
authors.lastname: Urayama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nagamatsu
authors.forename: Shuichi
authors.initials: S
authors.lastname: Takagahara
authors.forename: Justin H
authors.initials: JH
authors.lastname: Turner
authors.forename: Tohru
authors.initials: T
authors.lastname: Kozasa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sato
authors.forename: Toru
authors.initials: T
authors.lastname: Kawanishi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Inoue
authors.forename: Taku
authors.initials: T
authors.lastname: Nagao
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurose
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D017382:Reactive Oxygen Species; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C081643:candesartan