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J. Biol. Chem., Vol. 282, Issue 32, 23117-23128, August 10, 2007

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G12/13-mediated Up-regulation of TRPC6 Negatively Regulates Endothelin-1-induced Cardiac Myofibroblast Formation and Collagen Synthesis through Nuclear Factor of Activated T Cells Activation^*

Motohiro Nishida, Naoya Onohara, Yoji Sato, Reiko Suda, Mariko Ogushi, Shihori Tanabe, Ryuji Inoue^¶, Yasuo Mori^||, and Hitoshi Kurose¹

From the Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, the ^¶Department of Physiology, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka 814-0180, and the ^||Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan

Sustained elevation of [Ca²⁺]_i has been implicated in many cellular events. We previously reported that subunits of G₁₂ family G proteins (G_12/13) participate in sustained Ca²⁺ influx required for the activation of nuclear factor of activated T cells (NFAT), a Ca²⁺-responsive transcriptional factor, in rat neonatal cardiac fibroblasts. Here, we demonstrate that G_12/13-mediated up-regulation of canonical transient receptor potential 6 (TRPC6) channels participates in sustained Ca²⁺ influx and NFAT activation by endothelin (ET)-1 treatment. Expression of constitutively active G₁₂ or G₁₃ increased the expression of TRPC6 proteins and basal Ca²⁺ influx activity. The treatment with ET-1 increased TRPC6 protein levels through G_12/13, reactive oxygen species, and c-Jun N-terminal kinase (JNK)-dependent pathways. NFAT is activated by sustained increase in [Ca²⁺]_i through up-regulated TRPC6. A G_12/13-inhibitory polypeptide derived from the regulator of the G-protein signaling domain of p115-Rho guanine nucleotide exchange factor and a JNK inhibitor, SP600125, suppressed the ET-1-induced increase in expression of marker proteins of myofibroblast formation through a G_12/13-reactive oxygen species-JNK pathway. The ET-1-induced myofibroblast formation was suppressed by overexpression of TRPC6 and CA NFAT, whereas it was enhanced by TRPC6 small interfering RNAs and cyclosporine A. These results suggest two opposite roles of G_12/13 in cardiac fibroblasts. First, G_12/13 mediate ET-1-induced myofibroblast formation. Second, G_12/13 mediate TRPC6 up-regulation and NFAT activation that negatively regulates ET-1-induced myofibroblast formation. Furthermore, TRPC6 mediates hypertrophic responses in cardiac myocytes but suppresses fibrotic responses in cardiac fibroblasts. Thus, TRPC6 mediates opposite responses in cardiac myocytes and fibroblasts.

Received for publication, December 22, 2007 , and in revised form, May 25, 2007.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. N. and H. K.); from the Ministry of Health, Labour, and Welfare of Japan and the National Institute of Biomedical Innovation (MF-16) (to Y. S.); from the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), the Naito Foundation, and Takeda Science Foundation (to M. N.); and from the Astellas Foundation for Research on Metabolic Disorders and the Kimura Memorial Heart Foundation Research Grant for 2006 (to H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed. Tel./Fax: 81-92-642-6884; E-mail: kurose{at}phar.kyushu-u.ac.jp.

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