Mohamed Tamer M A, Zi Min, Prehar Sukhpal, Maqsood Arfa, Abou-Leisa Riham, Nguyen Loan, Pfeifer Gerd P, Cartwright Elizabeth J, Neyses Ludwig, Oceandy Delvac
Institute of Cardiovascular Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK Faculty of Pharmacy, Zagazig University, EL-Sharkiah, Egypt J David Gladstone Research Institutes, San Francisco, CA, USA.
Institute of Cardiovascular Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Cardiovasc Res. 2014 Jul 1;103(1):47-59. doi: 10.1093/cvr/cvu111. Epub 2014 Apr 28.
Tumour necrosis factor-α (TNF-α) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF-α receptors (TNFRs), the mechanism of TNF-α signal transmission is incompletely understood. The aim of this study was to investigate whether the tumour suppressor Ras-association domain family protein 1 isoform A (RASSF1A) modulates TNF-α signalling in cardiomyocytes.
We used RASSF1A knockout (RASSF1A(-/-)) mice and wild-type (WT) littermates in this study. Acute stimulation with a low dose of TNF-α (10 µg/kg iv) increased cardiac contractility and intracellular calcium transients' amplitude in WT mice. In contrast, RASSF1A(-/-) mice showed a blunted contractile response. Mechanistically, RASSF1A was essential in the formation of the TNFR complex (TNFRC), where it functions as an adaptor molecule to facilitate the recruitment of TNFR type 1-associated death domain protein and TNFR-associated factor 2 to form the TNF-α receptor complex. In the absence of RASSF1A, signal transmission from the TNF-α receptor complex to the downstream effectors, such as cytoplasmic phospholipase A2 and protein kinase A, was attenuated leading to the reduction in the activation of calcium handling molecules, such as L-type Ca(2+) channel and ryanodine receptors.
Our data indicate an essential role of RASSF1A in regulating TNF-α signalling in cardiomyocytes, with RASSF1A being key in the formation of the TNFRC and in signal transmission to the downstream targets.
肿瘤坏死因子-α（TNF-α）在心脏收缩力调节中起关键作用。尽管已知心肌细胞表达TNF-α受体（TNFRs），但TNF-α信号传导机制尚未完全明确。本研究旨在探讨肿瘤抑制因子Ras相关结构域家族蛋白1亚型A（RASSF1A）是否调节心肌细胞中的TNF-α信号传导。
本研究使用RASSF1A基因敲除（RASSF1A(-/-)）小鼠和野生型（WT）同窝小鼠。低剂量TNF-α（10μg/kg静脉注射）急性刺激可增加WT小鼠的心脏收缩力和细胞内钙瞬变幅度。相比之下，RASSF1A(-/-)小鼠的收缩反应减弱。机制上，RASSF1A在TNFR复合物（TNFRC）形成中必不可少，它作为衔接分子促进TNFR1相关死亡结构域蛋白和TNFR相关因子2的募集，以形成TNF-α受体复合物。在缺乏RASSF1A的情况下，从TNF-α受体复合物到下游效应器（如细胞质磷脂酶A2和蛋白激酶A）的信号传导减弱，导致钙处理分子（如L型Ca(2+)通道和兰尼碱受体）的激活减少。
我们的数据表明RASSF1A在调节心肌细胞TNF-α信号传导中起重要作用，RASSF1A在TNFRC形成及向下游靶点的信号传导中起关键作用。
