NR3C2 mediates oxidised low-density lipoprotein-induced human coronary endothelial cells dysfunction via modulation of NLRP3 inflammasome activation
NR3C2 mediates oxidised low-density lipoprotein-induced human coronary endothelial cells dysfunction via modulation of NLRP3 inflammasome activation
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DOI：
10.1080/08916934.2023.2189135
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发表时间：
2023-12-31
期刊：
影响因子：
3.5
通讯作者：
Chang, Chengdong
中科院分区：
文献类型：
--
作者：
Chen, Xiaofan;Li, Weidong;Chang, Chengdong
核受体亚家族3 C组成员2（NR 3C 2）已被揭示影响多种炎性疾病的进展，而NR 3C 2在冠状动脉疾病（CAD）中的功效在很大程度上仍未解决。本研究旨在阐明NR 3C 2在氧化低密度脂蛋白（ox-LDL）诱导的人冠状动脉内皮细胞（HCAECs）炎症中通过调节NACHT、LRR和PYD结构域蛋白3（NLRP 3）的可能机制。收集在我院行CT血管造影或冠状动脉造影疑似CAD的患者。将患者分为CAD和非CAD（NCAD）组。采用RT-qPCR检测两组患者外周血中NR 3C 2和NLRP 3的表达。用ox-LDL处理HCAEC建立模型。RT-qPCR检测NR 3C 2和NLRP 3在ox-LDL诱导的HCAEC中的表达。CCK-8法检测HCAECs增殖情况，流式细胞术检测HCAECs凋亡情况，ELISA法检测细胞培养上清中IL-1 β和IL-18的水平。这些因子在HCAECs增殖和凋亡以及炎症反应中的分子机制通过敲低和过表达系统进一步确定。通过ChIP和荧光素酶活性测定以及生物信息学分析确定NR 3C 2和NLRP 3之间的关系。冠心病患者血清NR 3C 2和NLRP 3水平升高。ox-LDL处理升高NR 3C 2水平，诱发细胞凋亡和炎症，并阻碍HCAECs中的细胞活力，而NR 3C 2的下调增加细胞活力，减少ox-LDL诱导的HCAECs炎症中的细胞凋亡和炎症反应。NR 3C 2水平与NLRP 3正相关，NR 3C 2通过转录提高NLRP 3表达。在ox-LDL诱导的HCAEC中，NLRP 3的过表达抵消了沉默NR 3C 2对细胞活力、细胞凋亡和炎症反应的影响。我们的研究强调NR 3C 2转录促进NLRP 3诱导ox-LDL诱导的HCAEC的炎症反应。
Nuclear receptor subfamily 3 group C member 2 (NR3C2) has been revealed to affect the progression of multiple inflammatory diseases, while NR3C2's efficacy in coronary artery disease (CAD) remains largely unsolved. The study intended to elucidate the possible mechanisms of NR3C2 in oxidised low density lipoprotein (ox-LDL)-induced inflammation in human coronary endothelial cells (HCAECs) via regulating NACHT, LRR, and PYD domains-containing protein 3 (NLRP3). Patients who underwent CT angiography or coronary angiography for suspected CAD in our hospital were collected. The patients were divided into the CAD and the non-CAD (NCAD) groups. The expression of NR3C2 and NLRP3 in the peripheral blood of patients in both groups was examined by RT-qPCR. HCAECs were treated with ox-LDL to establish the model. The expression of NR3C2 and NLRP3 in ox-LDL-induced HCAECs was tested by RT-qPCR. The proliferation of HCAECs was measured using CCK-8 assay, the apoptosis of HCAECs was assessed by flow cytometry, and the levels of inflammation-related factors IL-1 beta and IL-18 in the cell supernatant were evaluated by ELISA. The molecular mechanisms of these factors in the proliferation and apoptosis of HCAECs and in the inflammatory response were further determined by knockdown and overexpression systems. The relationship between NR3C2 and NLRP3 was determined by ChIP and luciferase activity assays and bioinformatics analysis. NR3C2 and NLRP3 levels were elevated in the serum of CAD patients. The ox-LDL treatment elevated NR3C2 levels, evoked apoptosis and inflammation, and impeded cell viability in HCAECs, whereas downregulation of NR3C2 increased cell viability and reduced apoptosis and inflammatory response in ox-LDL-induced inflammation in HCAECs. NR3C2 levels were positively correlated with NLRP3, and NR3C2 elevated NLRP3 expression through transcription. Overexpression of NLRP3 counteracted the impacts of silencing NR3C2 on cell viability, cell apoptosis, and inflammatory response in ox-LDL-induced HCAECs. Our research stresses that NR3C2 transcription promotes NLRP3 to induce inflammatory responses in ox-LDL-induced HCAECs.