This Article Full Text Full Text (PDF) All Versions of this Article: 91/10/961    most recent 01.RES.0000043282.39776.7Cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maruyama, Y. Articles by Kurose, H. Search for Related Content PubMed PubMed Citation Articles by Maruyama, Y. Articles by Kurose, H. Pubmed/NCBI databases Substance via MeSH Related Collections Hypertrophy Cardiovascular Pharmacology

(Circulation Research. 2002;91:961.)
© 2002 American Heart Association, Inc.

Integrative Physiology

G_12/13 Mediates ₁-Adrenergic Receptor–Induced Cardiac Hypertrophy

Yoshiko Maruyama, Motohiro Nishida, Yoshiyuki Sugimoto, Shihori Tanabe, Justin H. Turner, Tohru Kozasa, Teiji Wada, Taku Nagao, Hitoshi Kurose

From the Laboratory of Pharmacology and Toxicology (Y.M., M.N., Y.S., S.T., T.N., H.K.) and the Laboratory of Physiological Chemistry (T.W.), Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; the Department of Medicine (J.H.T.), Medical University of South Carolina, Charleston; and the Department of Pharmacology (T.K.), University of Illinois at Chicago. Dr Wada is now at Amgen Institute, Ontario Cancer Institute, and the Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; Dr Sugimoto is at Kyowa Hakko Inc, Shizuoka, Japan; Dr Nagao is at the National Institute of Health Sciences, Tokyo, Japan; and Dr Kurose is at the Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Correspondence to Hitoshi Kurose, PhD, Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail kurose{at}phar.kyushu-u.ac.jp

In neonatal cardiomyocytes, activation of the G_q-coupled ₁-adrenergic receptor (₁AR) induces hypertrophy by activating mitogen-activated protein kinases, including c-Jun NH₂-terminal kinase (JNK). Here, we show that JNK activation is essential for ₁AR-induced hypertrophy, in that ₁AR-induced hypertrophic responses, such as reorganization of the actin cytoskeleton and increased protein synthesis, could be blocked by expressing the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of JNK. We also identified the classes and subunits of G proteins that mediate ₁AR-induced JNK activation and hypertrophic responses by generating several recombinant adenoviruses that express polypeptides capable of inhibiting the function of specific G-protein subunits. ₁AR-induced JNK activation was inhibited by the expression of carboxyl terminal regions of G_q, G₁₂, and G₁₃. JNK activation was also inhibited by the G_q/11- or G_12/13-specific regulator of G-protein signaling (RGS) domains and by C3 toxin but was not affected by treatment with pertussis toxin or by expression of the carboxyl terminal region of G protein–coupled receptor kinase 2, a polypeptide that sequesters Gß. ₁AR-induced hypertrophic responses were inhibited by G_q/11- and G_12/13-specific RGS domains, C3 toxin, and the carboxyl terminal region of G protein–coupled receptor kinase 2 but not by pertussis toxin. Activation of Rho was inhibited by carboxyl terminal regions of G₁₂ and G₁₃ but not by G_q. Our findings suggest that ₁AR-induced hypertrophic responses are mediated in part by a G_12/13-Rho-JNK pathway, in part by a G_q/11-JNK pathway that is Rho independent, and in part by a Gß pathway that is JNK independent.

Key Words: c-Jun NH₂-terminal kinase • G₁₂ family G proteins • ₁-adrenergic receptors • hypertrophy

This article has been cited by other articles:

				M. Nishida, N. Onohara, Y. Sato, R. Suda, M. Ogushi, S. Tanabe, R. Inoue, Y. Mori, and H. Kurose G{alpha}12/13-mediated Up-regulation of TRPC6 Negatively Regulates Endothelin-1-induced Cardiac Myofibroblast Formation and Collagen Synthesis through Nuclear Factor of Activated T Cells Activation J. Biol. Chem., August 10, 2007; 282(32): 23117 - 23128. [Abstract] [Full Text] [PDF]

				A. Appert-Collin, S. Cotecchia, M. Nenniger-Tosato, T. Pedrazzini, and D. Diviani The A-kinase anchoring protein (AKAP)-Lbc-signaling complex mediates {alpha}1 adrenergic receptor-induced cardiomyocyte hypertrophy PNAS, June 12, 2007; 104(24): 10140 - 10145. [Abstract] [Full Text] [PDF]

				D. P. Del Re, S. Miyamoto, and J. H. Brown RhoA/Rho Kinase Up-regulate Bax to Activate a Mitochondrial Death Pathway and Induce Cardiomyocyte Apoptosis J. Biol. Chem., March 16, 2007; 282(11): 8069 - 8078. [Abstract] [Full Text] [PDF]

				K. Yoshioka, N. Sugimoto, N. Takuwa, and Y. Takuwa Essential Role for Class II Phosphoinositide 3-kinase {alpha}-Isoform in Ca2+-Induced, Rho- and Rho Kinase-Dependent Regulation of Myosin Phosphatase and Contraction in Isolated Vascular Smooth Muscle Cells Mol. Pharmacol., March 1, 2007; 71(3): 912 - 920. [Abstract] [Full Text] [PDF]

				A. Zeidan, S. Javadov, and M. Karmazyn Essential role of Rho/ROCK-dependent processes and actin dynamics in mediating leptin-induced hypertrophy in rat neonatal ventricular myocytes Cardiovasc Res, October 1, 2006; 72(1): 101 - 111. [Abstract] [Full Text] [PDF]

				J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]

				N. Wettschureck and S. Offermanns Mammalian G Proteins and Their Cell Type Specific Functions Physiol Rev, October 1, 2005; 85(4): 1159 - 1204. [Abstract] [Full Text] [PDF]

				N. Mizuno, H. Kokubu, M. Sato, A. Nishimura, J. Yamauchi, H. Kurose, and H. Itoh G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration PNAS, August 30, 2005; 102(35): 12365 - 12370. [Abstract] [Full Text] [PDF]

				T. Fujii, N. Onohara, Y. Maruyama, S. Tanabe, H. Kobayashi, M. Fukutomi, Y. Nagamatsu, N. Nishihara, R. Inoue, H. Sumimoto, et al. G{alpha}12/13-mediated Production of Reactive Oxygen Species Is Critical for Angiotensin Receptor-induced NFAT Activation in Cardiac Fibroblasts J. Biol. Chem., June 17, 2005; 280(24): 23041 - 23047. [Abstract] [Full Text] [PDF]

				M. Nishida, S. Tanabe, Y. Maruyama, S. Mangmool, K. Urayama, Y. Nagamatsu, S. Takagahara, J. H. Turner, T. Kozasa, H. Kobayashi, et al. 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 J. Biol. Chem., May 6, 2005; 280(18): 18434 - 18441. [Abstract] [Full Text] [PDF]

				A. T. K. Singh, A. Gilchrist, T. Voyno-Yasenetskaya, J. M. Radeff-Huang, and P. H. Stern G{alpha}12/G{alpha}13 Subunits of Heterotrimeric G Proteins Mediate Parathyroid Hormone Activation of Phospholipase D in UMR-106 Osteoblastic Cells Endocrinology, May 1, 2005; 146(5): 2171 - 2175. [Abstract] [Full Text] [PDF]

				Y.-N. Lee, C. C. Malbon, and H.-y. Wang G{alpha}13 Signals via p115RhoGEF Cascades Regulating JNK1 and Primitive Endoderm Formation J. Biol. Chem., December 24, 2004; 279(52): 54896 - 54904. [Abstract] [Full Text] [PDF]

				F. D Russell and P. Molenaar Investigation of signaling pathways that mediate the inotropic effect of urotensin-II in human heart Cardiovasc Res, September 1, 2004; 63(4): 673 - 681. [Abstract] [Full Text] [PDF]

				G. Selvetella, E. Hirsch, A. Notte, G. Tarone, and G. Lembo Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence Cardiovasc Res, August 15, 2004; 63(3): 373 - 380. [Abstract] [Full Text] [PDF]

				L. Barki-Harrington, C. Perrino, and H. A Rockman Network integration of the adrenergic system in cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 391 - 402. [Abstract] [Full Text] [PDF]

				Y. Kawanabe, N. Hashimoto, and T. Masaki Characterization of G proteins involved in activation of nonselective cation channels and arachidonic acid release by norepinephrine/{alpha}1A-adrenergic receptors Am J Physiol Cell Physiol, March 1, 2004; 286(3): C596 - C600. [Abstract] [Full Text] [PDF]