Background:Endothelial cells depend on glycolysis for much of their energy production. Impaired endothelial glycolysis has been associated with various vascular pathobiologies, including impaired angiogenesis and atherogenesis. IFN-γ (interferon-γ)–producing CD4⁺ and CD8⁺ T lymphocytes have been identified as the predominant pathological cell subsets in human atherosclerotic plaques. Although the immunologic consequences of these cells have been extensively evaluated, their IFN-γ–mediated metabolic effects on endothelial cells remain unknown. The purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine, IFN-γ, on human coronary artery endothelial cells.Methods:The metabolic effects of IFN-γ on primary human coronary artery endothelial cells were assessed by unbiased transcriptomic and metabolomic analyses combined with real-time extracellular flux analyses and molecular mechanistic studies. Cellular phenotypic correlations were made by measuring altered endothelial intracellular cGMP content, wound-healing capacity, and adhesion molecule expression.Results:IFN-γ exposure inhibited basal glycolysis of quiescent primary human coronary artery endothelial cells by 20% through the global transcriptional suppression of glycolytic enzymes resulting from decreased basal HIF1α (hypoxia-inducible factor 1α) nuclear availability in normoxia. The decrease in HIF1α activity was a consequence of IFN-γ–induced tryptophan catabolism resulting in ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF1β sequestration by the kynurenine-activated AHR (aryl hydrocarbon receptor). In addition, IFN-γ resulted in a 23% depletion of intracellular nicotinamide adenine dinucleotide in human coronary artery endothelial cells. This altered glucose metabolism was met with concomitant activation of fatty acid oxidation, which augmented its contribution to intracellular ATP balance by >20%. These metabolic derangements were associated with adverse endothelial phenotypic changes, including decreased basal intracellular cGMP, impaired endothelial migration, and a switch to a proinflammatory state.Conclusions:IFN-γ impairs endothelial glucose metabolism by altered tryptophan catabolism destabilizing HIF1, depletes nicotinamide adenine dinucleotide, and results in a metabolic shift toward increased fatty acid oxidation. This work suggests a novel mechanistic basis for pathological T lymphocyte–endothelial interactions in atherosclerosis mediated by IFN-γ, linking endothelial glucose, tryptophan, and fatty acid metabolism with the nicotinamide adenine dinucleotide balance and ATP generation and their adverse endothelial functional consequences.

中文翻译：

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干扰素-γ 通过色氨酸分解代谢损害人冠状动脉内皮葡萄糖代谢并激活脂肪酸氧化

背景：内皮细胞的大部分能量产生依赖于糖酵解。受损的内皮糖酵解与各种血管病理学相关，包括受损的血管生成和动脉粥样硬化形成。IFN-γ（干扰素-γ）——产生 CD4 ⁺和 CD8 ⁺T 淋巴细胞已被确定为人类动脉粥样硬化斑块中的主要病理细胞亚群。尽管这些细胞的免疫学后果已得到广泛评估，但它们对内皮细胞的 IFN-γ 介导的代谢作用仍然未知。本研究的目的是确定 T 淋巴细胞因子 IFN-γ 对人冠状动脉内皮细胞的代谢影响。方法：通过无偏转录组学评估 IFN-γ 对原代人冠状动脉内皮细胞的代谢作用代谢组学分析与实时细胞外通量分析和分子机制研究相结合。通过测量改变的内皮细胞内 cGMP 含量、伤口愈合能力和粘附分子表达来建立细胞表型相关性。结果：IFN-γ 暴露通过糖酵解酶的全局转录抑制抑制静止原代人冠状动脉内皮细胞的基础糖酵解 20%，这是由于常氧条件下基础 HIF1α（缺氧诱导因子 1α）核可用性降低所致。HIF1α 活性的降低是 IFN-γ 诱导的色氨酸分解代谢导致 ARNT（芳基烃受体核转运蛋白）/HIF1β 被犬尿氨酸激活的 AHR（芳基烃受体）螯合的结果。此外，IFN-γ 导致人冠状动脉内皮细胞中 23% 的细胞内烟酰胺腺嘌呤二核苷酸消耗。这种改变的葡萄糖代谢伴随着脂肪酸氧化的激活，这将其对细胞内 ATP 平衡的贡献增加了 >20%。这些代谢紊乱与不利的内皮表型变化相关，包括基础细胞内 cGMP 减少、内皮迁移受损和转为促炎状态。并导致代谢转变为增加脂肪酸氧化。这项工作为 IFN-γ 介导的动脉粥样硬化中病理性 T 淋巴细胞-内皮相互作用提供了一个新的机制基础，将内皮葡萄糖、色氨酸和脂肪酸代谢与烟酰胺腺嘌呤二核苷酸平衡和 ATP 生成及其不利的内皮功能后果联系起来。包括基础细胞内 cGMP 减少、内皮迁移受损和转为促炎状态。结论：IFN-γ 通过改变色氨酸分解代谢破坏内皮葡萄糖代谢，使 HIF1 不稳定，耗尽烟酰胺腺嘌呤二核苷酸，并导致代谢转变为增加脂肪酸氧化. 这项工作为 IFN-γ 介导的动脉粥样硬化中病理性 T 淋巴细胞-内皮相互作用提供了一个新的机制基础，将内皮葡萄糖、色氨酸和脂肪酸代谢与烟酰胺腺嘌呤二核苷酸平衡和 ATP 生成及其不利的内皮功能后果联系起来。包括基础细胞内 cGMP 减少、内皮迁移受损和转为促炎状态。结论：IFN-γ 通过改变色氨酸分解代谢破坏内皮葡萄糖代谢，使 HIF1 不稳定，耗尽烟酰胺腺嘌呤二核苷酸，并导致代谢转变为增加脂肪酸氧化. 这项工作为 IFN-γ 介导的动脉粥样硬化中病理性 T 淋巴细胞-内皮相互作用提供了一个新的机制基础，将内皮葡萄糖、色氨酸和脂肪酸代谢与烟酰胺腺嘌呤二核苷酸平衡和 ATP 生成及其不利的内皮功能后果联系起来。耗尽烟酰胺腺嘌呤二核苷酸，并导致代谢转变为增加脂肪酸氧化。这项工作为 IFN-γ 介导的动脉粥样硬化中病理性 T 淋巴细胞-内皮相互作用提供了一个新的机制基础，将内皮葡萄糖、色氨酸和脂肪酸代谢与烟酰胺腺嘌呤二核苷酸平衡和 ATP 生成及其不利的内皮功能后果联系起来。耗尽烟酰胺腺嘌呤二核苷酸，并导致代谢转变为增加脂肪酸氧化。这项工作为 IFN-γ 介导的动脉粥样硬化中病理性 T 淋巴细胞-内皮相互作用提供了一个新的机制基础，将内皮葡萄糖、色氨酸和脂肪酸代谢与烟酰胺腺嘌呤二核苷酸平衡和 ATP 生成及其不利的内皮功能后果联系起来。