Atheroprone flow enhances the endothelial-to-mesenchymal transition
Atheroprone flow enhances the endothelial-to-mesenchymal transition
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动脉粥样硬化流动增强内皮间质转化
DOI：
10.1152/ajpheart.00213.2018
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发表时间：
2018-11-01
影响因子：
4.8
通讯作者：
Shyy, John Y-J
中科院分区：
文献类型：
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作者：
Lai, Baochang;Li, Zhao;Shyy, John Y-J
内皮细胞向间充质细胞转化（EndoMT）是一种细胞过程，其特征在于内皮细胞标志基因表达减少，但间充质细胞标志基因表达增加。EndoMT参与内皮功能障碍和动脉粥样硬化的发病机制。为了研究动脉粥样硬化保护性脉动剪切应力（PS）和动脉粥样硬化振荡剪切应力（OS）下血管内皮细胞中EndoMT基因的动态表达，我们分析了来自多时间点剪切应力实验的RNA测序数据。这种涉及下一代测序的无偏分析证实了PS和OS在调节EndoMT基因方面具有相反的作用。进一步的实验验证与H2 O2和增益和功能丧失的方法表明，活性氧参与OS诱导的EndoMT，而AMP激活的蛋白激酶和sirtuin-1可以抑制OS诱导的EndoMT。此外，与PS相比，OS增加了von Willebrand因子、CD 31和钙粘蛋白5基因启动子区的DNA甲基化，但降低了钙粘蛋白2、成纤维细胞特异性蛋白1和波形蛋白的DNA甲基化。本研究的翻译意义建立在抗糖尿病药物metfomin和降胆固醇药物阿托伐他汀抑制培养的内皮细胞和小鼠血管内皮细胞中的EndoMT的能力上。新&值得注意的是我们的RNA测序数据提供了一个全基因组和无偏见的观点，即内皮细胞向间充质转化（EndoMT）的剪切应力调节。此外，表观遗传调节（例如，DNA甲基化）是剪切应力调节EndoMT的关键机制。这项研究的翻译含义是，心血管药物，如他汀类药物和二甲双胍具有类似的有益效果，动脉粥样硬化保护流通过减轻EndoMT。
The endothelial-to-mesenchymal transition (EndoMT) is a cellular process featuring decreased expression of endothelial marker genes but increased expression of mesenchymal marker genes. The EndoMT is involved in endothelial dysfunction and the pathogenesis of atherosclerosis. To investigate the dynamic expression of EndoMT genes in vascular endothelial cells under atheroprotective pulsatile shear stress (PS) and atheroprone oscillatory shear stress (OS), we analyzed RNA sequencing data from multitimepoint shear-stress experiments. This unbiased analysis involving next-generation sequencing confirmed that PS and OS had an opposite effect in regulating EndoMT genes. Further experimental validations with H2O2 and gain- and loss-of-function approaches indicated that reactive oxygen species are involved in OS-induced EndoMT, whereas AMP-activated protein kinase and sirtuin-1 could inhibit OS-induced EndoMT. Furthermore, compared with PS, OS increased the DNA methylation of the promoter regions of von Willebrand factor, CD31, and cadherin 5 genes but decreased that of cadherin 2, fibroblast-specific protein 1, and vimentin. The translational implication of the present study builds on the ability of the antidiabetic drug metfomin and cholesterol-lowering drug atorvastatin to suppress the EndoMT in cultured endothelial cells and in mouse aortas.NEW & NOTEWORTHY Our RNA sequencing data provided a genome-wide and unbiased view of' the shear stress regulation of the endothelial-to-mesenchymal transition (EndoMT) in the endothelium. Furthermore, epigenetic regulation (e.g., DNA methylation) is a key mechanism involved in shear stress-regulated EndoMT. The translational implication of this study is that cardiovascular medications such as statins and metformin have similar beneficial effects as that of atheroprotective flow by mitigating EndoMT.