Cardiovascular and Inflammation Biology Group, Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street London, NW1 0TU, UK.
Endocrine Signalling Group, Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK.
Biosensors (Basel). 2018 Sep 14;8(3):86. doi: 10.3390/bios8030086.
Cardiovascular diseases, including atherosclerosis, now account for more deaths in the Western world than from any other cause. Atherosclerosis has a chronic inflammatory component involving Th1 pro-inflammatory cytokines such as IFN-γ, which is known to induce endothelial cell inflammatory responses. On the other hand CNP, which acts via its receptors to elevate intracellular cGMP, is produced by endothelium and endocardium and is upregulated in atherosclerosis. It is believed to be protective, however its role in vascular inflammation is not well understood. The aim of this study was to investigate the effects of CNP on human endothelial cell inflammatory responses following IFN-γ stimulation. Human umbilical vein endothelial cells were treated with either IFN-γ (10 ng/mL) or CNP (100 nm), or both in combination, followed by analysis by flow cytometry for expression of MHC class I and ICAM-1. IFN-γ significantly increased expression of both molecules, which was significantly inhibited by CNP or the cGMP donor 8-Bromoguanosine 3',5'-cyclic monophosphate (1 µm). CNP also reduced IFN-γ mediated kynurenine generation by the IFN-γ regulated enzyme indoleamine-2,3-deoxygenase (IDO). We conclude that CNP downmodulates IFN-γ induced pro-inflammatory gene expression in human endothelial cells via a cGMP-mediated pathway. Thus, CNP may have a protective role in vascular inflammation and novel therapeutic strategies for CVD based on upregulation of endothelial CNP expression could reduce chronic EC inflammation.
心血管疾病，包括动脉粥样硬化，现在在西方世界导致的死亡比其他任何原因都多。动脉粥样硬化具有慢性炎症成分，涉及 Th1 促炎细胞因子，如 IFN-γ，已知其诱导内皮细胞炎症反应。另一方面，CNP 通过其受体作用升高细胞内 cGMP，由内皮细胞和心内膜产生，并在动脉粥样硬化中上调。它被认为是保护性的，然而，其在血管炎症中的作用尚未得到很好的理解。本研究旨在研究 CNP 对 IFN-γ刺激后人内皮细胞炎症反应的影响。用人脐静脉内皮细胞分别用 IFN-γ（10ng/mL）或 CNP（100nm）或两者联合处理，然后用流式细胞术分析 MHC Ⅰ类和 ICAM-1 的表达。IFN-γ显著增加了这两种分子的表达，而 CNP 或 cGMP 供体 8-溴鸟苷 3'，5'-环单磷酸（1µM）显著抑制了这种表达。CNP 还降低了 IFN-γ 调节的酶吲哚胺 2,3-双加氧酶（IDO）介导的 IFN-γ 介导致色氨酸的生成。我们得出结论，CNP 通过 cGMP 介导的途径下调 IFN-γ 诱导的人内皮细胞促炎基因表达。因此，CNP 可能在血管炎症中具有保护作用，基于内皮细胞 CNP 表达上调的 CVD 新型治疗策略可能会减少慢性 EC 炎症。
