ER stress dependent microparticles derived from smooth muscle cells promote endothelial dysfunction during thoracic aortic aneurysm and dissection.
ER stress dependent microparticles derived from smooth muscle cells promote endothelial dysfunction during thoracic aortic aneurysm and dissection.
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来自平滑肌细胞的内质网应激依赖性微粒在胸主动脉瘤和夹层过程中促进内皮功能障碍
DOI：
10.1042/cs20170252
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发表时间：
2017-06-01
期刊：
影响因子：
--
通讯作者：
Du J
中科院分区：
文献类型：
--
作者：
Jia LX;Zhang WM;Li TT;Liu Y;Piao CM;Ma YC;Lu Y;Wang Y;Liu TT;Qi YF;Du J
血管平滑肌细胞（SMC）变性是胸主动脉瘤和夹层（TAAD）的主要特征之一。我们和其他人已经表明，升高的内质网（ER）应激导致SMC丢失和TAAD形成，然而，SMC功能障碍如何导致内膜损伤，导致TAAD的机制仍有待探讨。在本研究中，体外试验表明，升高的机械拉伸（18%伸长率，3600个周期/小时）刺激ER应激反应和微粒（S）（MP）的生产从SMC和内皮细胞（EC）以时间依赖性的方式。用分离的MP处理EC导致失巢凋亡，这通过测量在水凝胶包被的板和对照板中培养的乙锭同二聚体（EthD-1）和钙黄绿素AM的荧光来确定。MP刺激EC还上调炎性分子（即血管细胞粘附分子-1（VCAM-1））、细胞间粘附分子-1（ICAM-1）、白细胞介素-1 β（IL-1β）和白细胞介素-6（IL-6））的mRNA水平。使用ER应激抑制剂或敲除CHOP可降低SMC中机械牵张诱导的MP产生。在体内，ER应激抑制剂或CHOP基因敲除抑制EC凋亡和炎性细胞浸润。此外，TAAD的形成也被ER应激抑制剂的给药所抑制。总之，我们的研究表明，升高的机械牵张诱导SMC中MP形成，导致内皮功能障碍，这是ER应力依赖性的。ER应激的抑制抑制了EC凋亡、主动脉炎症和TAAD的发展。
The degeneration of vascular smooth muscle cell(s) (SMC) is one of the key features of thoracic aortic aneurysm and dissection (TAAD). We and others have shown that elevated endoplasmic reticulum (ER) stress causes SMC loss and TAAD formation, however, the mechanism of how SMC dysfunction contributes to intimal damage, leading to TAAD, remains to be explored. In the present study, in vitro assay demonstrated that elevated mechanical stretch (18% elongation, 3600 cycles/h) stimulated the ER stress response and microparticle(s) (MP) production from both SMC and endothelial cell(s) (EC) in a time-dependent manner. Treatment of EC with isolated MP led to anoikis, which was determined by measuring the fluorescence of the ethidium homodimer (EthD-1) and Calcein AM cultured in hydrogel-coated plates and control plates. MP stimulation of EC also up-regulated the mRNA levels of inflammatory molecules (i.e. Vascular cellular adhesion molecular-1 (VCAM-1)), intercellular adhesion molecular-1 (ICAM-1), interleukin-1β (IL-1β), and interleukin-6 (IL-6)). Use of an ER stress inhibitor or knockout of CHOP decreased mechanical stretch-induced MP production in SMC. In vivo, administration of an ER stress inhibitor or knockout of CHOP suppressed both apoptosis of EC and the infiltration of inflammatory cells. Moreover, TAAD formation was also suppressed by the administration of an ER stress inhibitor. In conclusion, our study demonstrates that elevated mechanical stretch induces MP formation in SMC leading to endothelial dysfunction, which is ER stress dependent. The inhibition of ER stress suppressed EC apoptosis, inflammation in the aorta, and TAAD development.