TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy.
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+)-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+) 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+) oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca(2+) 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 Ca(2+) signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy.
Onohara
Naoya
N
Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka.
Nishida
Motohiro
M
Inoue
Ryuji
R
Kobayashi
Hiroyuki
H
Sumimoto
Hideki
H
Sato
Yoji
Y
Mori
Yasuo
Y
Nagao
Taku
T
Kurose
Hitoshi
H
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D020746:Calcium Channels, L-Type / Q000502:physiology; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D015640:Ion Channel Gating; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D020746:Calcium Channels, L-Type; D004075:Diglycerides; D050778:NFATC Transcription Factors; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C492145:Trpc6 protein, rat; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases