肺动脉高压患者肺动脉内皮细胞糖酵解增加、一氧化氮合成酶 O-GlcNAcylation 减少

S. Basehore, A. Clyne
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摘要

肺动脉高压(PAH)是一种主要影响女性的致命疾病。在 PAH 中,内皮细胞功能失调,血管扩张剂一氧化氮的生成减少,同时增殖增加。其他研究表明 PAH 会改变葡萄糖代谢。我们最近的研究表明,在血流紊乱的情况下,内皮细胞葡萄糖代谢增加会增加内皮细胞一氧化氮合酶(eNOS)(制造一氧化氮的酶)的 O-GlcNAcylation,从而减少一氧化氮的产生。因此,我们假设 PAH 内皮细胞中内皮糖酵解活性的升高会通过增加 eNOS O-GlcNAcylation 来减少一氧化氮的产生。我们培养了来自肺移植失败("非 PAH")和特发性 PAH 患者("PAH")的人肺动脉内皮细胞(HPAECs),并对每种细胞类型的糖酵解活性、一氧化氮产生量和 eNOS O-GlcNAcylation 进行了量化。我们的数据显示,与非 PAH HPAECs 相比,PAH HPAECs 有更高的葡萄糖摄取量和糖酵解代谢产物,而一氧化氮的产生量则有所下降。然而,PAH HPAECs 的 eNOS O-GlcNAcylation 和 O-GlcNAcylation 的底物 UDP-GlcNAc 均较低。有趣的是,与雄性 HPAECs 相比,雌性 HPAECs 的葡萄糖摄取量和 eNOS O-GlcNAcylation 都更高。这些数据表明,虽然 PAH 会改变内皮糖代谢,但 eNOS O-GlcNAcylation 与一氧化氮的减少无关。此外,来自男性和女性供体的 HPAECs 中葡萄糖代谢和蛋白质 O-GlcNAcylation 的差异可能与 PAH 的性双态性有关。
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Human Pulmonary Artery Endothelial Cells Increased Glycolysis and Decreased Nitric Oxide Synthase O-GlcNAcylation in Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a fatal disease that primarily affects women. In PAH, endothelial cells become dysfunctional, reducing production of the vasodilator nitric oxide while increasing proliferation. Other studies suggest altered glucose metabolism in PAH. Our recent study showed that increased endothelial glucose metabolism in disturbed flow increased O-GlcNAcylation of endothelial nitric oxide synthase (eNOS), the enzyme that makes nitric oxide, which then reduced nitric oxide production. We therefore hypothesized that elevated endothelial glycolytic activity in PAH endothelial cells would reduce nitric oxide production by increasing eNOS O-GlcNAcylation. We cultured human pulmonary artery endothelial cells (HPAECs) from failed lung transplant (“non-PAH”) and idiopathic PAH patients (“PAH”) and quantified glycolytic activity, nitric oxide production, and eNOS O-GlcNAcylation in each cell type. Our data show that PAH HPAECs had higher glucose uptake and glycolytic metabolites, as well as decreased nitric oxide production, compared to non-PAH HPAECs. However, PAH HPAECs had lower eNOS O-GlcNAcylation and UDP-GlcNAc, the substrate for O-GlcNAcylation. Interestingly, both glucose uptake and eNOS O-GlcNAcylation were higher in female as compared to male HPAECs. These data suggest that although endothelial glycolytic metabolism is altered in PAH, eNOS O-GlcNAcylation is not connected to decreased nitric oxide. In addition, differences in glucose metabolism and protein O-GlcNAcylation in HPAECs from male and female donors could relate to PAH sexual dimorphism.
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