TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy.
TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy.
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DOI：
10.3389/fphar.2018.00523
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发表时间：
2018
影响因子：
5.6
通讯作者：
Nishida M
中科院分区：
文献类型：
--
作者：
Sunggip C;Shimoda K;Oda S;Tanaka T;Nishiyama K;Mangmool S;Nishimura A;Numaga-Tomita T;Nishida M
由神经体液因素（包括血管紧张素II和内皮素-1）诱导的心脏肥大是心力衰竭的主要易感因素。这些配体主要通过二酰基甘油激活的瞬时受体电位典型3和6（TRPC 3/6）异源多聚体通道激活的钙依赖性钙调神经磷酸酶/活化T细胞核因子（NFAT）信号通路诱导新生大鼠心肌细胞（NRCMs）肥大生长。虽然细胞外核苷酸，腺苷5′-三磷酸（ATP），也被认为是最有效的钙动员配体，作用于嘌呤能受体，ATP从来没有引起心肌细胞肥大。在这里，我们表明，ATP诱导的一氧化氮（NO）的产生负调控NRCM中TRPC 3/6通道介导的肥大信号。NO合酶（NOS）的药理学抑制增强了ATP诱导的NFAT活性、蛋白质合成和脑利钠肽转录活性的增加。ATP显着增加NO的生产和蛋白激酶G（PKG）的活性相比，血管紧张素II和内皮素-1。我们发现ATP诱导的Ca ~（2+）信号需要肌醇1，4，5-三磷酸（IP 3）受体激活。有趣的是，TRPC 5的抑制，而不是TRPC 6衰减ATP诱导的激活的Ca 2 +/NFAT依赖的信号转导。由于TRPC 5的抑制减弱了ATP刺激的NOS激活，这些结果表明，由IP 3介导的TRPC 5通道激活的NO-cGMP-PKG轴是ATP刺激诱导的TRPC 3/6依赖性肥大信号转导的负调节的基础。
Cardiac hypertrophy, induced by neurohumoral factors, including angiotensin II and endothelin-1, is a major predisposing factor for heart failure. These ligands can induce hypertrophic growth of neonatal rat cardiomyocytes (NRCMs) mainly through Ca2+-dependent calcineurin/nuclear factor of activated T cell (NFAT) signaling pathways activated by diacylglycerol-activated transient receptor potential canonical 3 and 6 (TRPC3/6) heteromultimer channels. Although extracellular nucleotide, adenosine 5′-triphosphate (ATP), is also known as most potent Ca2+-mobilizing ligand that acts on purinergic receptors, ATP never induces cardiomyocyte hypertrophy. Here we show that ATP-induced production of nitric oxide (NO) negatively regulates hypertrophic signaling mediated by TRPC3/6 channels in NRCMs. Pharmacological inhibition of NO synthase (NOS) potentiated ATP-induced increases in NFAT activity, protein synthesis, and transcriptional activity of brain natriuretic peptide. ATP significantly increased NO production and protein kinase G (PKG) activity compared to angiotensin II and endothelin-1. We found that ATP-induced Ca2+ signaling requires inositol 1,4,5-trisphosphate (IP3) receptor activation. Interestingly, inhibition of TRPC5, but not TRPC6 attenuated ATP-induced activation of Ca2+/NFAT-dependent signaling. As inhibition of TRPC5 attenuates ATP-stimulated NOS activation, these results suggest that NO-cGMP-PKG axis activated by IP3-mediated TRPC5 channels underlies negative regulation of TRPC3/6-dependent hypertrophic signaling induced by ATP stimulation.
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影响因子：
11.4
作者：
Nishida, M;Sugimoto, K;Mori, Y
通讯作者：
Mori, Y
影响因子：
4.6
作者：
Kitajima N;Numaga-Tomita T;Watanabe M;Kuroda T;Nishimura A;Miyano K;Yasuda S;Kuwahara K;Sato Y;Ide T;Birnbaumer L;Sumimoto H;Mori Y;Nishida M
通讯作者：
Nishida M
DOI：
10.1073/pnas.162100799
发表时间：
2002-08-20
影响因子：
11.1
作者：
Fiedler, B;Lohmann, SM;Wollert, KC
通讯作者：
Wollert, KC
影响因子：
4.8
作者：
Bush, Erik W.;Hood, David B.;McKinsey, Timothy A.
通讯作者：
McKinsey, Timothy A.
DOI：
10.1073/pnas.0712316105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Colella, Matilde;Grisan, Francesca;Pozzan, Tullio
通讯作者：
Pozzan, Tullio