Department of Pharmacology, School of Pharmacy, University of Granada, 18071, Granada, Spain.
Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA, Granada, Spain.
Arthritis Res Ther. 2017 Dec 6;19(1):268. doi: 10.1186/s13075-017-1478-7.
We tested whether GW0742, a peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) agonist, improves endothelial dysfunction induced by plasma from patients with systemic lupus erythematosus (SLE) involving the inhibition of endoplasmic reticulum (ER) stress.
A total of 12 non-pregnant women with lupus and 5 non-pregnant healthy women (controls) participated in the study. Cytokines and double-stranded DNA autoantibodies (anti-dsDNA) were tested in plasma samples. Endothelial cells, isolated from human umbilical cord veins (HUVECs), were used to measure nitric oxide (NO), intracellular reactive oxygen species (ROS) production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and ER stress markers.
Interferon-γ, interleukin-6, and interleukin-12 levels were significantly increased in plasma from patients with SLE with active nephritis (AN), as compared to both patients with SLE with inactive nephritis (IN) and the control group. The NO production stimulated by both the calcium ionophore A23187 and insulin was significantly reduced in HUVECs incubated with plasma from patients with AN-SLE as compared with the control group. Plasma from patients with IN-SLE did not modify A23187-stimulated NO production. Increased ROS production and NADPH oxidase activity were found in HUVECs incubated with plasma from patients with AN-SLE, which were suppressed by the ER stress inhibitor 4-PBA and the NADPH oxidase inhibitors, apocynin and VAS2870. GW0742 incubation restored the impaired NO production, the increased ROS levels, and the increased ER stress markers induced by plasma from patients with AN-SLE. These protective effects were abolished by the PPARβ/δ antagonist GSK0660 and by silencing PPARβ/δ.
PPARβ/δ activation may be an important target to control endothelial dysfunction in patients with SLE.
我们测试了过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）激动剂 GW0742 是否通过抑制内质网（ER）应激来改善由系统性红斑狼疮（SLE）患者血浆引起的内皮功能障碍。
共有 12 名非妊娠狼疮患者和 5 名非妊娠健康女性（对照组）参与了这项研究。在血浆样本中测试了细胞因子和双链 DNA 自身抗体（抗 dsDNA）。从人脐静脉内皮细胞（HUVEC）中分离出内皮细胞，用于测量一氧化氮（NO）、细胞内活性氧（ROS）产生、烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性和 ER 应激标志物。
与 SLE 无活动期肾炎（IN）患者和对照组相比，活动期肾炎（AN）患者的血浆中干扰素-γ、白细胞介素-6 和白细胞介素-12 水平显著升高。与对照组相比，用 AN-SLE 患者的血浆孵育的 HUVEC 中，钙离子载体 A23187 和胰岛素刺激的 NO 产生明显减少。IN-SLE 患者的血浆未改变 A23187 刺激的 NO 产生。在用 AN-SLE 患者的血浆孵育的 HUVEC 中发现 ROS 产生增加和 NADPH 氧化酶活性增加，这些变化被 ER 应激抑制剂 4-PBA 和 NADPH 氧化酶抑制剂 apocynin 和 VAS2870 抑制。GW0742 孵育恢复了由 AN-SLE 患者的血浆引起的受损的 NO 产生、增加的 ROS 水平和增加的 ER 应激标志物。这些保护作用被 PPARβ/δ 拮抗剂 GSK0660 和沉默 PPARβ/δ 所消除。
PPARβ/δ 激活可能是控制 SLE 患者内皮功能障碍的重要靶点。
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