Roles of notch signaling pathway and endothelial-mesenchymal transition in vascular endothelial dysfunction and atherosclerosis
Roles of notch signaling pathway and endothelial-mesenchymal transition in vascular endothelial dysfunction and atherosclerosis
复制标题
Notch信号通路和内皮间质转化在血管内皮功能障碍和动脉粥样硬化中的作用。
DOI：
10.26355/eurrev_201810_16062
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发表时间：
2018-10-01
影响因子：
3.3
通讯作者：
Chun, J.
中科院分区：
文献类型：
--
作者：
Lin, Q-Q.;Zhao, J.;Chun, J.
目的：探讨Notch信号通路在血管内皮功能障碍和动脉粥样硬化过程中内皮-间质转化（EndMT）中的作用。材料与方法：用外源性Notch同源物1 （Notchl）因子处理人冠状动脉内皮细胞（HCAEC），激活Notchl通路，在显微镜下观察细胞形态学变化。Western blot检测相关蛋白的表达变化。采用18只SD大鼠进行体内实验，采用GSI因子特异性抑制Notch通路的激活。将大鼠随机分为正常饮食（ND）组、高脂饮食（HFD）组、高脂饮食+GSI （HFD+GSI）组，每组6只。采用苏木精伊红（H&E）染色法观察各治疗组大鼠心脏主动脉形态。采用实时聚合酶链反应（RT-PCR）和Western blot检测各组大鼠主动脉组织中Notchl、Hest、VE-cadherin和a-SMA mRNA和蛋白水平的表达。结果：Notchl处理hcaec后，内皮蛋白VE-cadherin水平显著降低，间质蛋白α - sma水平显著升高。在动物模型中，高脂饮食喂养两个月的大鼠主动脉出现明显的动脉粥样硬化斑点。而饲喂相同饮食并给予Notch通路GSI抑制剂的小鼠，其动脉粥样硬化症状明显减少。与ND组比较，HFD组大鼠主动脉Notchl、Hes1、α - sma mRNA及蛋白表达水平显著升高，内皮标志物VE-cadherin表达水平显著降低。与HFD组大鼠比较。HFD+GSI组大鼠Notchl、Hes1和α - sma表达水平显著降低。结论：Notch信号通路的激活可诱导EndMT的进展，促进动脉粥样硬化病变的发展。
OBJECTIVE: To investigate the role of the Notch signaling pathway on the endothelial-mesenchymal transition (EndMT) during vascular endothelial dysfunction and atherosclerosis.MATERIALS AND METHODS: Human coronary artery endothelial cells (HCAEC) were treated with the exogenous Notch homolog 1 (Notchl) factor to activate the Notchl pathway, and cells were then observed under the microscope for morphologic changes. Changes in the expression of related proteins were detected by Western blot. In vivo experiments were performed using 18 Sprague Dawley (R) (SD) rats, and GSI factor was used to specifically inhibit Notch pathway activation. Rats were used and randomly divided into three groups: normal diet (ND) group, high-fat diet (HFD) group, and high-fat diet + GSI (HFD+GSI) group, 6 rats in each group. Hematoxylin and eosin (H&E) staining was used to examine the cardiac aortic morphology of the rats in each treatment group. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to detect the expression of Notchl, Hest VE-cadherin and a-SMA in the aortic tissues of rats in each group at mRNA and protein levels, respectively.RESULTS: After HCAECs were treated with Notchl, endothelial protein levels of VE-cadherin were significantly decreased and levels of the interstitial protein alpha-SMA were significantly increased. In the animal model, the rats fed with high-fat diet for two months presented obvious atherosclerosis spots in their aorta. but those fed with the same diet and treated with GSI inhibitor of Notch pathway showed significantly fewer atherosclerosis signs. Compared with ND group, mRNA and protein expression levels of Notchl, Hes1 and alpha-SMA were significantly increased, and the expression levels of endothelial marker VE-cadherin were significantly de-creased in aortas of rats in HFD group. Compared with the rats in HFD group. the rats in HFD+GSI group showed significantly reduced expression levels of Notchl, Hes1 and alpha-SMA.CONCLUSIONS: The activation of Notch signaling pathway can induce the EndMT progression and promote the development of atherosclerotic lesions.