The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes
The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes
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DOI：
10.1016/j.cardiores.2005.05.015
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发表时间：
2005-10-01
影响因子：
10.8
通讯作者：
Binah, O
中科院分区：
文献类型：
--
作者：
Barac, YD;Zeevi-Levin, N;Binah, O
目的：心肌肥厚是对机械负荷增加的一种代偿性反应。由于Fas受体活化是压力和容量超负荷诱导的肥大的重要组成部分，因此破译潜在的信号通路是至关重要的。在我们以前的工作基础上，发现在小鼠和大鼠心室肌细胞中，Fas激活3 h引起的电生理紊乱和舒张期[Ca（2+）]（i）升高依赖于Fas ->磷脂酶C（PLC）-> 1，4，5-三磷酸肌醇（1，4，5-IP（3））->肌浆网（SR）[Ca（2+）]（i）释放途径，我们检验了这一途径在Fas介导的肥大中也是关键的假说。采用RT-PCR、Western blot、免疫荧光和Fura-2荧光等方法分析培养的新生大鼠心室肌细胞（NRVM）24 h Fas活化的影响。Fas激活增加细胞核表面积、心房钠尿肽和连接蛋白43（Cx43）mRNA、总Cx43和非磷酸化Cx43蛋白水平以及肌节肌动蛋白，均表明肥大。同时，Fas激活降低SERCA 2a、ryanodine受体（RyR）和核IP（3）R3的mRNA。此外，Fas激活引起NFAT核转位。U 73122、xestospongin C（1，4，5-IP（3）通路阻断剂）、genistein和PI 3 K阻断剂LY 294002均能抑制细胞肥大。结论：Fas介导的细胞肥大依赖于1，4，5-IP（3）通路，该通路与PI 3 K/AKT/GSK 3 β通路在功能上相互联系。这两种途径共同作用导致NFAT核移位和随后的肥大。(c)2005年欧洲心脏病学会。Elsevier B. V.出版，保留所有权利。
Objective: Cardiac hypertrophy is a compensatory response to increased mechanical load. Since Fas receptor activation is an important component in hypertrophy induced by pressure- and volume-overload, deciphering the underlying signaling pathways is of prime importance. Based on our previous work showing that in mice and rats ventricular myocytes the electrophysiological disturbances and diastolic [Ca(2+)](i)-rise caused by 3 h of Fas activation are dependent on the Fas -> phospholipase C (PLC) -> 1,4,5-inositol trisphosphate (1,4,5-IP(3)) -> sarcoplasmic reticulum (SR) [Ca(2+)](i) release pathway, we tested the hypothesis that this pathway is also critical for Fas-mediated hypertrophy.Methods: The effects of 24 h Fas activation in cultured neonatal rat ventricular myocytes (NRVM) were analyzed by means of RT-PCR, Western blot, immunofluorescence and fura-2 fluorescence.Results: Fas activation increased nuclei surface area, atrial natriuretic peptide and connexin43 (Cx43) mRNA, the protein levels of total Cx43 and non-phosphorylated Cx43, and sarcomeric actin, all indicating hypertrophy. Concomitantly, Fas activation decreased mRNA of SERCA2a, the ryanodine receptor (RyR) and nuclear IP(3)R3. Further, Fas activation caused NFAT nuclear translocation. The hypertrophy was abolished by U73122, xestospongin C (blockers of the 1,4,5-IP(3) pathway), genistein and by the PI3K blocker LY294002.Conclusions: Fas-mediated hypertrophy is dependent on the 1,4,5-IP(3) pathway, which is functionally inter-connected to the PI3K/AKT/ GSK3 beta pathway. Both pathways act in concert to cause NFAT nuclear translocation and subsequent hypertrophy. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.