Published online before print October 24, 2002, doi: 10.1161/01.RES.0000043282.39776.7C
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Submitted on March 28, 2002
Revised on October 14, 2002
Accepted on October 14, 2002
G
12/13 Mediates 
1-Adrenergic Receptor-Induced Cardiac Hypertrophy
Yoshiko Maruyama ;
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.
* To whom correspondence should be addressed. E-mail: kurose{at}phar.kyushu-u.ac.jp.
In neonatal cardiomyocytes, activation of the Gq-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 Gq, G12, and G13. JNK activation was also inhibited by the Gq/11- or G12/13-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 Gq/11- and G12/13-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 Gq. Our findings suggest that 1AR-induced hypertrophic responses are mediated in part by a G12/13-Rho-JNK pathway, in part by a Gq/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
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