Department of Internal Medicine/Cardiology, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany;
Am J Physiol Heart Circ Physiol. 2013 Dec 1;305(11):H1592-9. doi: 10.1152/ajpheart.00018.2013. Epub 2013 Sep 16.
Atherosclerosis is a chronic inflammatory disease. Cardiovascular risk factors such as hyperglycemia, hyperlipidemia, and arterial hypertension induce endothelial dysfunction with alterations in endothelial biosecretion and immune behavior. The aim of this study is to elucidate whether glucose-induced modifications of endothelial biosecretory and immune functions are regulated by interactions of endothelial cells (ECs) with their extracellular matrix [ECs plated on polystyrene-coated tissue culture plates (TC-EC) vs. ECs embedded within three-dimensional (3-D) collagen-based matrixes (3D-EC)]. In the absence of glucose, IFN-γ-induced phosphorylation of JAK and STAT proteins and human leukocyte antigen (HLA)-DR expression were lower in 3D-EC compared with TC-EC. Inversely, the expression of suppressor of cytokine signaling proteins (SOCS)-1 and -3 were significantly higher in naïve 3D-EC compared with naïve TC-EC. IFN-γ-induced upregulation of SOCS proteins was further amplified by the 3-D environment. Glucose significantly augmented IFN-γ-dependent signaling pathways in TC-EC. IFN-γ-induced phosphorylation of JAK and STAT proteins as well as HLA-DR expression by ECs in low- and high-glucose medium was significantly lower in 3-D than in two-dimensional environment. Glucose increased SOCS expression in TC-EC and 3D-EC to the same extent, such that expression levels in 3D-EC exceeded SOCS-1 and -3 expression in TC-EC by 1.6-2.5-fold. In conclusion, low- and high-glucose concentrations amplify IFN-γ-induced signaling pathways in TC-EC. Increased SOCS expression raises the threshold for IFN-γ to induce HLA-DR expression in a 3-D environment. This immunoprotective effect is maintained even in states of experimental hyperglycemia.
动脉粥样硬化是一种慢性炎症性疾病。心血管危险因素，如高血糖、高血脂和动脉高血压，会导致内皮功能障碍，内皮生物分泌和免疫行为发生改变。本研究旨在阐明葡萄糖是否通过内皮细胞（EC）与其细胞外基质的相互作用来调节内皮细胞生物分泌和免疫功能的改变[铺在聚苯乙烯涂层组织培养板上的 EC（TC-EC）与嵌入三维（3-D）基于胶原基质中的 EC（3D-EC）]。在无葡萄糖的情况下，与 TC-EC 相比，3D-EC 中 IFN-γ 诱导的 JAK 和 STAT 蛋白磷酸化以及人类白细胞抗原（HLA）-DR 的表达较低。相反，在未成熟的 3D-EC 中，抑制细胞因子信号蛋白（SOCS）-1 和 -3 的表达明显高于未成熟的 TC-EC。SOCS 蛋白的 IFN-γ 诱导表达在 3-D 环境中进一步放大。葡萄糖显著增强了 TC-EC 中 IFN-γ 依赖性信号通路。在低糖和高糖培养基中，IFN-γ 诱导的 ECs 的 JAK 和 STAT 蛋白磷酸化以及 HLA-DR 表达在 3-D 中比在 2-D 环境中明显更低。葡萄糖增加了 TC-EC 和 3D-EC 中 SOCS 的表达，使 3D-EC 中 SOCS 的表达比 TC-EC 中 SOCS-1 和 -3 的表达高 1.6-2.5 倍。总之，低糖和高糖浓度会放大 TC-EC 中 IFN-γ 诱导的信号通路。SOCS 表达的增加提高了 HLA-DR 在 3-D 环境中表达的阈值。即使在实验性高血糖状态下，这种免疫保护作用也能维持。
