Activating transcription factor 3 SUMOylation is involved in angiotensin II-induced endothelial cell inflammation and dysfunction
Activating transcription factor 3 SUMOylation is involved in angiotensin II-induced endothelial cell inflammation and dysfunction
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激活转录因子 3 SUMO 化参与血管紧张素 II 诱导的内皮细胞炎症和功能障碍
DOI：
10.1016/j.yjmcc.2016.02.001
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发表时间：
2016
影响因子：
5
通讯作者：
Gao Ping-Jin
中科院分区：
文献类型：
--
作者：
Zhang Ze-Bei;Ruan Cheng-Chao;Chen Dong-Rui;Zhang Ke;Yan Chen;Gao Ping-Jin
转录激活因子3（Activating transcription factor 3，ATF 3）是一种由多种环境应激诱导的适应性反应蛋白，参与多种疾病的发病机制。然而，ATF 3 SUMO化在高血压诱导的血管损伤中的作用仍然知之甚少。我们研究了ATF 3 SUMO化在血管内皮细胞中的作用。血管紧张素II（Ang II）诱导的人脐静脉内皮细胞（HUVECs）中ATF 3和SUMO 1的表达增加。显微镜分析进一步显示，ATF 3和SUMO 1的表达上调，并在血管紧张素II诱导的高血压小鼠的胸主动脉内皮共定位。然而，在体外和体内，Ang II诱导的ATF 3和SUMO 1的上调被Ang II I型受体拮抗剂奥美沙坦阻断。此外，血管紧张素II诱导ATF 3 SUMO化赖氨酸42，这是SUMO 1依赖性。ATF 3 SUMO化减弱了ATF 3的泛素化，反过来又促进了ATF 3蛋白的稳定性。ATF 3或SUMO 1敲低抑制Ang II诱导的炎症分子如肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和IL-8的表达。野生型ATF 3而非ATF 3-K42 R（SUMO化缺陷突变体）减少了一氧化氮（NO）的产生，这是EC功能的关键指标。同时，银杏酸，SUMO化的抑制剂，增加内皮细胞NO的产生，并显着改善血管紧张素II诱导的高血压小鼠的主动脉血管舒张。我们的研究结果表明，在体外和体内，ATF 3 SUMO化参与Ang II诱导的EC炎症和功能障碍，通过抑制ATF 3泛素化和增加ATF 3蛋白的稳定性。
Activating transcription factor 3 (ATF3) is an adaptive-response protein induced by various environmental stresses and is implicated in the pathogenesis of many disease states. However, the role of ATF3 SUMOylation in hypertension-induced vascular injury remains poorly understood. Here we investigated the function of ATF3 SUMOylation in vascular endothelial cells (ECs). The expression of ATF3 and small ubiquitin-like modifier 1 (SUMO1) was increased in angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVECs). Microscopic analyses further revealed that the expression of ATF3 and SUMO1 is upregulated and colocalized in the endothelium of thoracic aortas from Ang II-induced hypertensive mice. However, Ang II-induced upregulation of ATF3 and SUMO1 in vitro and in vivo was blocked by Ang II type I receptor antagonist olmesartan. Moreover, Ang II induced ATF3 SUMOylation at lysine 42, which is SUMO1 dependent. ATF3 SUMOylation attenuated ATF3 ubiquitination and in turn promoted ATF3 protein stability. ATF3 or SUMO1 knockdown inhibited Ang II-induced expression of inflammatory molecules such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8. Wild type ATF3 but not ATF3-K42R (SUMOylation defective mutant) reduced the production of nitric oxide (NO), a key indicator of EC function. Consistently, ginkgolic acid, an inhibitor of SUMOylation, increased NO production in HUVECs and significantly improved vasodilatation of aorta from Ang II-induced hypertensive mice. Our findings demonstrated that ATF3 SUMOylation is involved in Ang II-induced EC inflammation and dysfunction in vitro and in vivo through inhibiting ATF3 ubiquitination and increasing ATF3 protein stability.