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J. Biol. Chem., Vol. 280, Issue 24, 23041-23047, June 17, 2005

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G12/13-mediated Production of Reactive Oxygen Species Is Critical for Angiotensin Receptor-induced NFAT Activation in Cardiac Fibroblasts^*

Tomomi Fujii, Naoya Onohara, Yoshiko Maruyama, Shihori Tanabe, Hiroyuki Kobayashi, Masashi Fukutomi, Yuichi Nagamatsu, Naoki Nishihara, Ryuji Inoue¶, Hideki Sumimoto||, Futoshi Shibasaki**, Taku Nagao, Motohiro Nishida, and Hitoshi Kurose

From the Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Laboratory of Cellular Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, ^¶Department of Pharmacology, Graduate School of Medicine, Kyushu University, Fukuoka 812-8582, ^||Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, ^**Department of Molecular Cell Physiology, The Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, and National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan

Angiotensin II (Ang II) activates multiple signaling pathways leading to hyperplasia of cardiac fibroblasts. Reactive oxygen species (ROS) produced by Ang II stimulation are assumed to play pivotal roles in this process. Here, we show that ROS mediate Ang II-induced activation of nuclear factor of activated T cells (NFAT) in rat cardiac fibroblasts. Ang II-induced NFAT activation was suppressed by diphenyleneiodonium (an NADPH oxidase inhibitor), dominant negative (DN)-Rac, DN-p47^phox, and an inhibitor of G_12/13 (G_12/13-specific regulator of G protein signaling domain of p115RhoGEF, p115-regulator of G protein signaling (RGS)). Stimulation of Ang II receptor increased the intracellular ROS level in a Rac- and p47^phox-dependent manner. Because p115-RGS suppressed Ang II-induced Rac activation, Ang II receptor-coupled G_12/13 mediated NFAT activation through ROS production by Rac activation. Ang II-induced nuclear translocation of the green fluorescent protein (GFP)-tagged amino-terminal region of NFAT4 (GFP-NFAT4) was suppressed by p115-RGS or BAPTA but not by diphenyleneiodonium. The expression of constitutively active (CA)-G_12/13, CA-G translocation ₁₃, or CA-Rac increased the nuclear of GFP-NFAT4. These results suggest that NFAT activity is regulated by both Ca²⁺-dependent and ROS-dependent pathways. Furthermore, activation of c-Jun NH₂-terminal kinase (JNK) induced by Ang II stimulation is required for NFAT activation because Ang II-induced NFAT activation was inhibited by SP600125, a selective JNK inhibitor. These results indicate that Ang II stimulates the nuclear translocation and activation of NFAT by integrated pathways including the activation of G_12/13, Rac, NADPH oxidase, and JNK and that G_12/13-mediated ROS production is essential for NFAT transcriptional activation.

Received for publication, August 16, 2004 , and in revised form, March 14, 2005.

^* This work was supported in part by a research grant (to M. N. and H. Kurose) from the Ministry of Education, Science, Sports, and Culture of Japan and in part by a grant (to M. N.) from the Kurozumi Medical Foundation, the Nakajima Memorial Foundation, and the Mochida Memorial Foundation for Medical and Pharmaceutical Research. 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.

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

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