Ulinastatin attenuates monocyte-endothelial adhesion via inhibiting ROS transfer between the neighboring vascular endothelial cells mediated by Cx43
Ulinastatin attenuates monocyte-endothelial adhesion via inhibiting ROS transfer between the neighboring vascular endothelial cells mediated by Cx43
复制标题
乌司他丁通过抑制 Cx43 介导的邻近血管内皮细胞之间的 ROS 转移来减弱单核细胞内皮粘附
DOI：
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发表时间：
2020
影响因子：
2.2
通讯作者：
Xiao Lunhua
中科院分区：
文献类型：
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作者：
Ding Hong;Jiang Yu;Jiang Yumei;Yuan Dongdong;Xiao Lunhua
乌司他丁因其良好的抗炎和抗氧化作用而被广泛应用于胰腺炎和脓毒症的治疗。然而，它对动脉粥样硬化，一种炎症性血管疾病的影响，很少报道。因此，在本研究中，我们探讨乌司他丁对单核细胞-内皮细胞粘附的影响，动脉粥样硬化的启动。我们使用U937单核细胞和血管紧张素II刺激的人脐静脉内皮细胞（HUVECs）建立单核细胞-内皮细胞粘附模型。采用不同方法改变U937-HUVECs的缝隙连接蛋白43（Cx43）的功能、ROS水平、JAK 2/STAT 3信号通路的激活及其下游MMP 2和MMP 9的表达，观察乌司他丁对U937-HUVECs粘附及粘附分子的影响。结果表明，乌司他丁可通过抑制Cx43的功能，减少相邻HUVECs之间ROS的传递。随着ROS水平的降低，JAK 2/STAT 3信号通路及其下游MMP 2和MMP 9表达下调。最终，重要的粘附分子表达，如VCAM-1，ICAM-1，sVCAM-1和sICAM-1，以及U937-HUVECs粘附均降低。由此可见，乌司他丁抑制粘附分子的表达和单核细胞-内皮细胞粘附，其机制与乌司他丁抑制Cx43介导的ROS在邻近血管内皮细胞间的传递，导致JAK 2/STAT 3信号通路失活，其下游MMP 2和MMP 9表达降低有关。
Ulinastatin is widely used in the treatment of pancreatitis and sepsis, because of its excellent anti-inflammatory and antioxidant effects. However, its effects on atherosclerosis, an inflammatory vascular disease, are rarely reported. Therefore, in present study, we explored effects of ulinastatin on monocyte-endothelial adhesion, the initiator of atherosclerosis. We used U937 monocytes and angiotensin II-stimulated human umbilical vein endothelial cells (HUVECs) to build the model of monocyte-endothelial adhesion. Different methods were used to change the function of connexin43 (Cx43), the level of ROS, the activation of JAK2/STAT3 signaling pathway and its downstream MMP2 and MMP9 expression, and then the influences of ulinastatin on U937-HUVECs adhesion and the adhesion molecules were observed. The results showed that ulinastatin could attenuate ROS transmission between the neighboring HUVECs via inhibiting Cx43 function. With the decrease of ROS, JAK2/STAT3 signaling pathway and its downstream MMP2 and MMP9 expression were downregulated. Ultimately, important adhesion molecules expression, such as VCAM-1, ICAM-1, sVCAM-1 and sICAM-1, and U937-HUVECs adhesion, were both reduced. Thus, we can conclude that ulinastatin attenuates adhesion molecules expression and monocyte-endothelial adhesion, mechanism of which is related that ulinastatin inhibits ROS transfer between the neighboring vascular endothelial cells mediated by Cx43, resulting in the inactivation of JAK2/STAT3 signaling pathway, and its downstream MMP2 and MMP9 expression decrease.