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 Ca 2 þ -responsive transcriptional factor. It is believed that phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP 3 ) is responsible for Ca 2 þ increase that is necessary for NFAT activation. However, we demonstrate that PLC-mediated production of diacylglycerol (DAG) but not IP 3 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 Ca 2 þ oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca 2 þ 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 DAGinduced Ca 2 þ signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy.

Sustained elevation of [Ca 2؉ ] i has been implicated in many cellular events. We previously reported that ␣ subunits of G 12 family G proteins (G␣ 12/13 ) participate in sustained Ca 2؉ influx required for the activation of nuclear factor of activated T cells (NFAT), a Ca 2؉ -responsive transcriptional factor, in rat neonatal cardiac fibroblasts. Here, we demonstrate that G␣ 12/13 -me-

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