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  • The EMBO Journal (2006) 25, 5305 - 5316
  • doi:10.1038/sj.emboj.7601417

Published online: 2 November 2006

TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy

Naoya Onohara1, Motohiro Nishida1, Ryuji Inoue2, Hiroyuki Kobayashi1, Hideki Sumimoto3, Yoji Sato4, Yasuo Mori5, Taku Nagao4 and Hitoshi Kurose1

  1. Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka
  2. Department of Physiology, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan
  3. Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Japan
  4. National Institute of Health Sciences, Setagaya, Tokyo, Japan
  5. Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan

Correspondence to:

Hitoshi Kurose, Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel./Fax: +81 92 642 6884; E-mail: kurose@phar.kyushu-u.ac.jp

Received 10 February 2006; Accepted 11 October 2006

Angiotensin (Ang) II participates in the pathogenesis of heart failure through induction of cardiac hypertrophy. Ang II-induced hypertrophic growth of cardiomyocytes is mediated by nuclear factor of activated T cells (NFAT), a Ca2+-responsive transcriptional factor. It is believed that phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP3) is responsible for Ca2+ increase that is necessary for NFAT activation. However, we demonstrate that PLC-mediated production of diacylglycerol (DAG) but not IP3 is essential for Ang II-induced NFAT activation in rat cardiac myocytes. NFAT activation and hypertrophic responses by Ang II stimulation required the enhanced frequency of Ca2+ oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca2+ channel. Patch clamp recordings from single myocytes revealed that Ang II activated DAG-sensitive TRPC-like currents. Among DAG-activating TRPC channels (TRPC3, TRPC6, and TRPC7), the activities of TRPC3 and TRPC6 channels correlated with Ang II-induced NFAT activation and hypertrophic responses. These data suggest that DAG-induced Ca2+ signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy.

  • Keywords:

    • angiotensin,
    • cardiac hypertrophy,
    • diacylglycerol,
    • L-type Ca2+ channel,
    • TRPC