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

TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy
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DOI：
10.1038/sj.emboj.7601417
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发表时间：
2006-11-15
期刊：
EMBO JOURNAL
影响因子：
11.4
通讯作者：
Kurose, Hitoshi
Kurose, Hitoshi
中科院分区：
生物学1区
文献类型：
--
作者：
Onohara, Naoya;Nishida, Motohiro;Kurose, Hitoshi

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血管紧张素（Ang） II通过诱导心脏肥厚参与心力衰竭的发病机制。Ang ii诱导的心肌细胞肥厚生长是由活化T细胞核因子（NFAT）介导的，这是一种Ca2+应答转录因子。人们认为磷脂酶C（PLC）介导的肌醇-1,4,5-三磷酸（IP3）的产生是NFAT激活所必需的Ca2+增加的原因。然而，我们证明了plc介导的二酰基甘油（DAG）而不是IP3的产生是Ang ii诱导的大鼠心肌细胞NFAT激活所必需的。Ang II刺激下的NFAT激活和肥厚反应需要通过激活dag敏感的TRPC通道，膜去极化触发Ca2+振荡频率增强，从而导致l型Ca2+通道的激活。来自单个肌细胞的膜片钳记录显示Ang II激活了dag敏感的trpc样电流。在dag激活的TRPC通道（TRPC3、TRPC6和TRPC7）中，TRPC3和TRPC6通道的活性与Ang ii诱导的NFAT激活和肥厚反应相关。这些数据表明，dag通过TRPC3和TRPC6诱导的Ca2+信号通路对于Ang ii诱导的NFAT激活和心脏肥厚是必不可少的。
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.