Department of Biomedical Engineering, The City College of New York, New York, NY, 10031, USA.
Department of Infection, Immunity and Cardiovascular Disease, INSIGNEO Institute for In Silico Medicine, and the Bateson Centre, University of Sheffield, Sheffield, UK.
Cardiovasc Drugs Ther. 2019 Apr;33(2):231-237. doi: 10.1007/s10557-019-06863-3.
Endothelial cell (EC) dysfunction (enhanced inflammation, proliferation and permeability) is the initial trigger for atherosclerosis. Atherosclerosis shows preferential development near branches and bends exposed to disturbed blood flow. By contrast, sites that are exposed to non-disturbed blood flow are atheroprotected. Disturbed flow promotes atherosclerosis by promoting EC dysfunction. Blood flow controls EC function through transcriptional and post-transcriptional mechanisms that are incompletely understood.
We identified the developmental transcription factors Twist1 and GATA4 as being enriched in EC at disturbed flow, atheroprone regions of the porcine aorta in a microarray study. Further work using the porcine and murine aortae demonstrated that Twist1 and GATA4 expression was enhanced at the atheroprone, disturbed flow sites in vivo. Using controlled in vitro flow systems, the expression of Twist1 and GATA4 was enhanced under disturbed compared to non-disturbed flow in cultured cells. Disturbed flow promoted Twist1 expression through a GATA4-mediated transcriptional mechanism as revealed by a series of in vivo and in vitro studies. GATA4-Twist1 signalling promoted EC proliferation, inflammation, permeability and endothelial-to-mesenchymal transition (EndoMT) under disturbed flow, leading to atherosclerosis development, as shown in a combination of in vitro and in vivo studies using GATA4 and Twist1-specific siRNA and EC-specific GATA4 and Twist1 Knock out (KO) mice.
We revealed that GATA4-Twist1-Snail signalling triggers EC dysfunction and atherosclerosis; this work could lead to the development of novel anti-atherosclerosis therapeutics.
内皮细胞（EC）功能障碍（增强炎症、增殖和通透性）是动脉粥样硬化的初始触发因素。动脉粥样硬化在分支和弯曲处优先发展，这些部位暴露于紊乱的血流中。相比之下，暴露于未受干扰血流的部位则具有抗动脉粥样硬化作用。紊乱的血流通过促进 EC 功能障碍促进动脉粥样硬化的发展。血流通过不完全了解的转录和转录后机制来控制 EC 功能。
我们在微阵列研究中发现，发育转录因子 Twist1 和 GATA4 在受干扰血流的 EC 中富集，在猪主动脉的易发生动脉粥样硬化的区域富集。使用猪和鼠主动脉的进一步研究表明，Twist1 和 GATA4 的表达在体内易发生动脉粥样硬化的受干扰血流部位增强。使用受控的体外流动系统，在培养细胞中，与非干扰流动相比，Twist1 和 GATA4 的表达在干扰流动下增强。通过一系列体内和体外研究，发现干扰流通过 GATA4 介导的转录机制促进 Twist1 的表达。在体外和体内研究中，使用 GATA4 和 Twist1 特异性 siRNA 和 EC 特异性 GATA4 和 Twist1 敲除（KO）小鼠，GATA4-Twist1 信号促进 EC 增殖、炎症、通透性和内皮到间充质转化（EndoMT），导致动脉粥样硬化的发展。
我们揭示了 GATA4-Twist1-Snail 信号触发 EC 功能障碍和动脉粥样硬化；这项工作可能会导致新型抗动脉粥样硬化治疗药物的开发。
