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. 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. Ang II 1The abbreviations used are: Ang II, angiotensin II; ATR, angiotensin receptor; AT1R, angiotensin type 1 receptor; CA, constitutively active; DCF, 2′,7′-dichlorofluorescein diacetate; DPI, diphenyleneiodonium; DN, dominant negative; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; GRK2, G protein-coupled receptor kinase 2; GST, glutathione S-transferase; GST-TPR, GST fusion protein with TPR domain of protein phosphatase 5; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MOI, multiplicity of infection; PAK, p21-activated kinase; Prx, peroxiredoxin; PTX, pertussis toxin; RGS, regulator of G protein signaling; ROCK, Rho-associated kinase; ROS, reactive oxygen species; TPR, tetratricopeptide repeat. is a bioactive peptide involved in cardiac hypertrophy (1Paradis P. Dali-Youcef N. Paradis F.W. Thibault G. Nemer M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 931-936Crossref PubMed Scopus (316) Google Scholar). Receptor stimulation by Ang II is assumed to activate Gq and Gi and turns on various signaling cascades dependent on cell types. Many groups have reported the regulation of MAPKs including JNK (2Schmitz U. Berk B.C. Trends. Endocrinol. Metab. 1997; 8: 261-266Abstract Full Text PDF PubMed Scopus (53) Google Scholar, 3Kudoh S. Komuro I. Mizuno T. Yamazaki T. Zou Y. Shiojima I. Takekoshi N. Yazaki Y. Circ. Res. 1997; 80: 139-146Crossref PubMed Scopus (151) Google Scholar), ERK (4Sadoshima J. Qiu Z. Morgan J.P. Izumo S. Circ. Res. 1995; 76: 1-15Crossref PubMed Scopus (390) Google Scholar, 5Li X. Lee J.W. Graves L.M. Earp H.S. EMBO J. 1998; 17: 2574-2583Crossref PubMed Scopus (144) Google Scholar), and p38 MAPK (6Ushio-Fukai M. Alexander R.W. Akers M. Griendling K.K. J. Biol. Chem. 1998; 273: 15022-15029Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar) in a variety of cells (7Eguchi S. Dempsey P.J. Frank G.D. Motley E.D. Inagami T. J. Biol. 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ROS such as hydrogen peroxide and oxygen radicals play various roles in living cells as a second messenger to elicit physiological responses or as a toxic intermediate leading to cellular damage (12Abe J. Berk B.C. Trends. Cardiovasc. Med. 1998; 8: 59-64Crossref PubMed Scopus (247) Google Scholar). Recent studies suggest that ROS work as regulators of signal transduction (13Takemoto M Node K Nakagami H Liao Y Grimm M Takemoto Y. Kitakaze M. Liao J.K. J. Clin. Investig. 2001; 108: 1429-1437Crossref PubMed Scopus (460) Google Scholar, 14Griendling K.K. Ushio-Fukai M. Regul. Pept. 2000; 91: 21-27Crossref PubMed Scopus (362) Google Scholar). We have reported that heterotrimeric Gi/o proteins are putative target molecules of ROS (15Nishida M. Maruyama Y. Tanaka R. Kontani K. Nagao T. Kurose H. Nature. 2000; 408: 492-495Crossref PubMed Scopus (230) Google Scholar, 16Nishida M. Schey K.L. Takagahara S. Kontani K. Katada T. Urano Y. Nagano T. Nagao T. Kurose H. J. Biol. Chem. 2002; 277: 9036-9042Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Although Ang II produces ROS in vascular smooth muscle cells and cardiac myocytes (6Ushio-Fukai M. Alexander R.W. Akers M. Griendling K.K. J. Biol. Chem. 1998; 273: 15022-15029Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 17Rajagopalan S. Kurz S. Münzel T. Tarpey M. Freeman B.A. Griendling K.K. Harrison D.G. J. Clin. Investig. 1996; 97: 1916-1923Crossref PubMed Scopus (2181) Google Scholar, 18Griendling K.K. Minieri C.A. Ollerenshaw J.D. Alexander R.W. Circ. Res. 1994; 74: 1141-1148Crossref PubMed Scopus (2422) Google Scholar), the molecular mechanism of ROS production and the identification of ROS target molecules are largely unknown. Rac, one of the small GTP-binding proteins, is believed to participate in the production of ROS by activating NADPH oxidase in neutrophil (19Bokoch G.M. Knaus U.G. Trends Biochem. Sci. 2003; 28: 502-508Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar). Previous findings have demonstrated that one of the Rac effector PAKs mediates JNK activation by Ang II, and PAK phosphorylates a subunit of the NADPH oxidase complex (20Schmitzs U. Thömmes K. Beier I. Wagner W. Sachinidis A. Düsing R. Vetter H. J. Biol. Chem. 2001; 276: 22003-22010Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). MAPKs are activated by Rac as well as RhoA and Raf-1, and the resulting activation of MAPKs induces hypertrophic responses through the activation of intracellular signaling cascades (21Nishida M. Nagao T. Kurose H. Biochem. Biophys. Res. Commun. 1999; 262: 350-354Crossref PubMed Scopus (18) Google Scholar, 22Coso O.A. Chiariello M. Yu J.-C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1572) Google Scholar, 23Minden A. Lin A. McMahon M. Lange-Carter C Dérijard B. Davis R.J. 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S. A. 1996; PubMed Scopus Google Scholar). of was the of JNK, ERK, and p38 MAPK rat neonatal cardiac myocytes rat as (15Nishida M. Maruyama Y. Tanaka R. Kontani K. Nagao T. Kurose H. Nature. 2000; 408: 492-495Crossref PubMed Scopus (230) Google Scholar). The of JNK was as Y. M. Y. S. T. T. Nagao T. Kurose H. Circ. Res. 2002; 91: PubMed Scopus Google Scholar, K. Maruyama Y. M. S. Takagahara S. T. Y. Nagao T. Kurose H. Mol. 2003; PubMed Scopus Google Scholar). ERK and p38 MAPK activation by Y. M. Y. S. T. T. Nagao T. Kurose H. Circ. Res. 2002; 91: PubMed Scopus Google Scholar, K. Maruyama Y. M. S. Takagahara S. T. Y. Nagao T. Kurose H. Mol. 2003; PubMed Scopus Google Scholar). The of the was and with of ROS by Ang II Receptor production was with the as K. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). The on and for with The an of was by a of Rac of Rac was by the of and M.A. 2000; PubMed Google Scholar) with a the by Ang II and in 1 and of domain. was with for The and in Rac was with of Rho activation was by the of Maruyama Y. M. Y. S. T. T. Nagao T. Kurose H. Circ. Res. 2002; 91: PubMed Scopus Google Scholar). by Ang II for 1 and in 1 1 The of cell was with of domain and for The was and in Rho was with of cells in with rat type and with or RGS in with or or with activation of was by the of Y. H. M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Ang II the cells with of 1 1 1 and of The cell for and the with for The was and in was with intracellular of was as (21Nishida M. Nagao T. Kurose H. Biochem. Biophys. Res. Commun. 1999; 262: 350-354Crossref PubMed Scopus (18) Google Scholar, K. Maruyama Y. M. S. Takagahara S. T. Y. Nagao T. Kurose H. Mol. 2003; PubMed Scopus Google Scholar). the cells on and with in the for The cells with and of cells and with a of the for of with in results are as the The with by or of by three or Ang II-induced MAPK the signal transduction leading to MAPK activation by Ang II the and of MAPK activation determined. with Ang II in a activation of ERK, JNK, and p38 MAPK The of Ang II to activate ERK, JNK, or p38 MAPK different between three ERK, JNK, and p38 MAPK activation and These results that Ang II stimulation activated three MAPKs in cardiac ROS Ang II-induced JNK and p38 MAPK examined which MAPK requires ROS for activation. of ROS is NADPH oxidase which is activated by receptor we examined the of such as NADPH oxidase and on MAPK activation. Ang II-induced ERK activation was not by these However, Ang II-induced activation of p38 MAPK and JNK was inhibited by three and We have also that the expression of II inhibited Ang II-induced JNK activation but not ERK activation not These results indicate that JNK and p38 MAPK activation are to ROS and suggest that ROS by NADPH oxidase is for Ang II-induced JNK and p38 MAPK activation. of Gα12/13 by the of which G protein is involved in Ang II-induced MAPK activation, a variety of that G signaling Among or was used to Gα12/13 or the of and RGS and Ang II-stimulated in was in the of extracellular Ang II stimulation was in the of extracellular the in the activation of C completely the in but did not A and did not affect the in intracellular the of is specific for the in These results suggest that but not C activation through Gαq. We have also examined the of signaling of Gα12/13 such as and has not been we the activation of Gα12/13 by Ang II has been reported that Gα12/13 activation be by of activated Gα12/13 the TPR domain of protein phosphatase type Y. H. M. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). we examined Ang II Gα12/13 activation by as a of the of by The of was completely by but not by RGS domain specific for Gα12/13 and the RGS domain in active the mechanism of by is between and for the of that did not affect the Ang II-induced in is that the active of of G12/13 by ATR and stimulation rapidly activated The activation a and for The Ang II-induced activation was completely inhibited by but not by the RGS domain of has the to of Gα12/13, the mechanism of by is the of also that AG1478 did not Ang II-stimulated activation that the EGF receptor is not involved in activation. Furthermore, stimulation of ATR also activated in rat cardiac myocytes The activation a 1 and to the Ang II-induced activation was completely inhibited by but not by These results indicate that stimulation of not Gq but also and that Ang II-induced activation. G12/13 Ang II-induced JNK and p38 MAPK examined Gα12/13 is involved in Ang II-induced MAPK activation. Ang II-induced ERK activation was not by but the activation of JNK and p38 MAPK was inhibited by We also used to and expression of did not affect Ang II-induced JNK activation We also that Ang II-induced p38 MAPK activation was to or 2; not These results suggest that the activation of JNK and p38 MAPK is mediated by Gα12/13 but not and These results indicate that ATR with and Gα12/13 signal transduction leading to JNK and p38 MAPK activation. of JNK and p38 MAPK by Gα12/13 the relationship between Gα12/13 and ROS in Ang II-induced JNK and p38 MAPK activation. of or in activation of three MAPKs that activated or activation of MAPKs in neonatal cardiac Furthermore, Gα12- or Gα13-induced activation of p38 MAPK and JNK but not ERK was to In JNK and p38 MAPK activation was not by These results are with the that activation of Gα12/13 by ATR stimulation JNK and p38 MAPK through ROS production. ROS by ATR examined ATR stimulation produces ROS in rat neonatal cardiomyocytes. that of Ang II intracellular of The of ROS by Ang II stimulation was with the of by Ang II stimulation ROS to and and inhibited ROS production However, the Ang II-induced ROS production was not by These results indicate that Gα12/13 but not mediates Ang II-induced ROS production. Furthermore, expression of or with inhibited Ang II-induced ROS production, that NADPH oxidase mediates Ang II-induced ROS production. Gα12/13 Rac to JNK and p38 MAPK examined the of Rac in Ang II-induced MAPK activation. of inhibited Ang II-induced activation of JNK and p38 MAPK, but not ERK inhibited Ang II-induced ROS production Rac mediate Ang II-induced JNK and p38 MAPK activation through ROS production. Rac activation be by the domain of PAK that is one of the Rac Rac activation was by angiotensin II which 1 and to the not the expression of completely inhibited Ang II-induced activation of JNK and p38 MAPK but not ERK Rac activation was inhibited by but not by PTX, and The Rac of cells was for Rac with has been reported by A. K. R. Marshall Sugden P.H. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). These results suggest that G12/13 mediate Ang II-induced Rac activation. Rho Ang II-induced Rac inhibited JNK, p38 MAPK, and Rac activation, we that Gα12/13 activate JNK, p38 MAPK, and Rac through Rho activation. Rho is by C3 toxin that of The expression of C3 toxin inhibited Ang II-stimulated JNK and Rac activation A and These results indicate that Rho mediates Rac and JNK activation by ATR Rho various kinases including ROCK, we examined mediates Ang II-induced Rac activation T. M. T. K. M. M. T. K. A. K. EMBO J. 1996; 15: PubMed Scopus Google Scholar). A inhibitor, inhibited Rac activation These results suggest that Ang II-induced Rac activation is mediated by Rho and activation of Furthermore, stimulation of ATR with Ang II activated Rho by which was completely inhibited by but not and ROS production is inhibited by Ang II-induced activation participate in ROS production. These results also suggest that Rac activation is of Rho activation. ATR and of EGF Receptor for Ang II-induced JNK II-induced JNK activation was inhibited by but not by that JNK was activated by type 1 of ATR has been reported that EGF receptor an role in G protein-coupled MAPK activation including (7Eguchi S. Dempsey P.J. Frank G.D. Motley E.D. Inagami T. J. Biol. Chem. 2001; 276: 7957-7962Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar). the of EGF receptor transactivation, we used an inhibitor of EGF receptor kinase AG1478 did not affect Ang II-stimulated activation JNK activation, ROS production, Rho activation, and Rac activation inhibited Rac activation, the These results suggest that EGF receptor is not involved in Ang II-induced JNK activation through Gα12/13-mediated activation in cardiac We demonstrated in the present study that Ang II-induced MAPK activation was mediated by a signal transduction Ang II Gα12/13 Rho Rac ROS MAPK We that ROS are by Gα12/13-mediated Rac activation, and ROS participate in JNK and p38 MAPK but not ERK activation. Previous findings that Ang II stimulation produces ROS in vascular smooth muscle cells (6Ushio-Fukai M. Alexander R.W. Akers M. Griendling K.K. J. Biol. Chem. 1998; 273: 15022-15029Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 17Rajagopalan S. Kurz S. Münzel T. Tarpey M. Freeman B.A. Griendling K.K. Harrison D.G. J. Clin. Investig. 1996; 97: 1916-1923Crossref PubMed Scopus (2181) Google Scholar) and the role of ROS as a of Ang II (6Ushio-Fukai M. Alexander R.W. Akers M. Griendling K.K. J. Biol. Chem. 1998; 273: 15022-15029Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 14Griendling K.K. Ushio-Fukai M. Regul. Pept. 2000; 91: 21-27Crossref PubMed Scopus (362) Google Scholar). The present study is with the that ROS are of Ang II We demonstrated that the of Ang II-induced ROS production in neonatal cardiac myocytes is NADPH because a inhibitor of NADPH oxidase JNK and p38 MAPK activation by Ang II The expression of and three MAPKs in rat cardiac myocytes is by the that JNK through the stimulation of an upstream kinase of JNK Lee N. PubMed Scopus Google Scholar). Furthermore, or activation of JNK and p38 MAPK was inhibited by NADPH oxidase Ang II-induced JNK and p38 MAPK activation was inhibited by we the activation that NADPH is to and reactive species that participate in JNK and p38 MAPK activation A EGF receptor kinase AG1478 that JNK activation not requires EGF receptor cardiac S. H. Y. H. Y. Y. I. Tanaka Y. S. Y. A. S. T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Google Scholar) reported that Ang II JNK through Rac, and In with JNK activation, ERK activation in cardiac requires EGF receptor through and activation. The present study cardiac myocytes demonstrated that Ang II-induced JNK activation was not inhibited by We demonstrated that Ang II-induced activation, Rho activation, Rac activation, and ROS production not inhibited by AG1478 and These results suggest that EGF receptor is not for Ang II-induced JNK and p38 MAPK activation through Gα12/13-mediated ROS production. The present study demonstrated that Rho and Rac activation. On the other hand, the negative regulation of Rac by Rho and has been by M M. M. H. S. J. Biol. 1998; PubMed Scopus Google Scholar). reported that and in that regulated the and Rac The mechanism of Rac by is unknown. However, different types of that are regulated by in and cardiac we also that a inhibitor inhibited Ang II-induced ROS production not the present study also that mediates Ang II-induced JNK and p38 MAPK activation through Rac activation. cells with PTX, the active of Rac was in the of stimulation The mechanism of Rac by is unknown. of be mitogenic of is an toxin; is the that and of that to the to cells and has a mitogenic the Rac activation be by the mitogenic of inhibited Ang II-induced ROS production and activation of JNK and p38 The that ROS production JNK and p38 MAPK activation. JNK and p38 MAPK activation requires However, Rac is believed to be involved in various signaling pathways other ROS production Rac is an of PAK leading to JNK activation (20Schmitzs U. Thömmes K. Beier I. Wagner W. Sachinidis A. Düsing R. Vetter H. J. Biol. Chem. 2001; 276: 22003-22010Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). We that Rac signaling pathways such as ROS production and PAK activation, and activation of pathways is required for JNK and p38 MAPK activation. The that G12/13 proteins are involved in Ang signaling has been also by A. G. S. Circ. Res. 2000; PubMed Scopus Google Scholar, N. P. G. J. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). A. G. S. Circ. Res. 2000; PubMed Scopus Google Scholar) have reported that angiotensin II stimulation the of and in of smooth muscle The present study that activate We demonstrated that of EGF receptor or did not affect Ang II-stimulated activation. N. P. G. J. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) also reported that a the peptide did not affect Ang II-induced Rac activation G12/13 not participate in JNK and p38 MAPK activation by Ang is thought to mediate Ang II-induced We demonstrated that expression of three MAPKs in rat neonatal cardiomyocytes. However, the present study did not role of in Ang II JNK and p38 MAPK activation. Zou Y. Komuro I. Yamazaki T. S. R. W. Shiojima I. Y. K. T. Yazaki Y. Circ. Res. 1998; PubMed Scopus Google Scholar) have reported that and protein kinase C mediate Ang II-induced ERK activation in rat cardiac is to that the mechanism of Ang II-induced MAPK activation is different between three mediates ERK activation, and Gα12/13 mediates JNK and p38 MAPK activation. The of JNK or p38 MAPK activation in of Ang II-induced hypertrophic responses Y. M. Y. S. T. T. Nagao T. Kurose H. Circ. Res. 2002; 91: PubMed Scopus Google Scholar, M.A. S. R. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). be to on pathways the for the of hypertrophic responses Ang II receptor In we have demonstrated a signal transduction pathway of Ang II-induced JNK and p38 MAPK G12/13 Rac ROS JNK and p38 The signaling between Gα12/13 and ROS in cardiac myocytes a of Ang II signaling We R. J. S. G. K. S. H. M. and M.
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