High Glucose Induces Endothelial COX2 and iNOS Expression via Inhibition of Monomethyltransferase SETD8 Expression
High Glucose Induces Endothelial COX2 and iNOS Expression via Inhibition of Monomethyltransferase SETD8 Expression
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高葡萄糖通过抑制单甲基转移酶 SETD8 表达诱导内皮 COX2 和 iNOS 表达
DOI：
10.1155/2020/2308520
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发表时间：
2020-02-24
影响因子：
4.3
通讯作者：
Miao, Changhong
中科院分区：
文献类型：
--
作者：
Qi, Jie;Wu, Qichao;Miao, Changhong
环氧合酶2（COX 2）和诱导型一氧化氮合酶（iNOS）的过度表达导致内皮细胞凋亡，从而介导高血压病血管内皮损伤。E26转化特异性序列转录因子-1（ESE-1）属于E26转化特异性转录因子家族，参与COX 2和iNOS基因的转录。我们的前期研究表明，SET结构域蛋白8（SETD 8）下调参与高糖介导的人脐静脉内皮细胞（HUVECs）内皮炎症。在这里，我们报告说，SETD 8在高血压诱导的COX 2和iNOS表达中起着重要作用。在HUVECs中，ESE-1表达的上调与高糖介导的凋亡以及COX 2和iNOS表达有关。高糖抑制了SETD 8的表达，并且SETD 8的过表达减弱了高糖处理的效果。一致地，SETD 8的RNA沉默导致相反的效果。此外，发现SETD 8与特异性蛋白1（SP1）相互作用。阻断SP1可防止高糖介导的内皮损伤。从机制上讲，我们通过ChIP测定表明，H4 K20 me 1（SETD 8的下游靶标）和SP1在ESE-1启动子区域富集。荧光素酶报告基因分析表明，SETD 8过表达减弱了ESE-1启动子活性，并增强了siSP 1对ESE-1启动子活性的抑制作用。总的来说，我们的数据表明，SETD 8与SP1相互作用，共同调节ESE-1的表达，这是参与高血压介导的内皮细胞凋亡的HUVECs。
Cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS) overexpression results in endothelial apoptosis, thus mediating vascular endothelial injury in hyperglycaemia. E26 transformation-specific sequence transcription factor-1 (ESE-1), which belongs to the E26 transformation-specific family of transcription factors, has been demonstrated to be involved in COX2 and iNOS gene transcription. Our previous study indicated that SET domain-containing protein 8 (SETD8) downregulation is involved in high glucose-mediated endothelial inflammation in human umbilical vein endothelial cells (HUVECs). Here, we report that SETD8 plays a major role in hyperglycaemia-induced COX2 and iNOS expression. In HUVECs, upregulation of ESE-1 expression was related to high glucose-mediated apoptosis and COX2 and iNOS expression. High glucose inhibited SETD8 expression, and overexpression of SETD8 diminished the effects of high glucose treatment. Consistently, RNA silencing of SETD8 led to the opposite effect. Furthermore, SETD8 was found to interact with specificity protein 1 (SP1). Blockade of SP1 protected against high glucose-mediated endothelial injury. Mechanistically, we showed that H4K20me1, a downstream target of SETD8, and SP1 were enriched at the ESE-1 promoter region by ChIP assay. Luciferase reporter assays indicated that SETD8 overexpression attenuated ESE-1 promoter activity and augmented the inhibitory effect of siSP1 on ESE-1 promoter activity. In general, our data indicate that SETD8 interacts with SP1 to coregulate ESE-1 expression, which is involved in hyperglycaemia-mediated endothelial apoptosis in HUVECs.