Basehore Sarah E, Clyne Alisa Morss
School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
Int J Transl Med (Basel). 2024 Mar;4(1):140-151. doi: 10.3390/ijtm4010007. Epub 2024 Feb 2.
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.
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，减少了血管舒张剂一氧化氮的产生，同时增加了细胞增殖。其他研究表明PAH中存在葡萄糖代谢改变。我们最近的研究表明，紊乱血流中内皮葡萄糖代谢增加会增加内皮型一氧化氮合酶（eNOS，即产生一氧化氮的酶）的O-连接N-乙酰葡糖胺化，进而减少一氧化氮的产生。因此，我们推测PAH内皮细胞中内皮糖酵解活性升高会通过增加eNOS的O-连接N-乙酰葡糖胺化来减少一氧化氮的产生。我们培养了来自肺移植失败患者（“非PAH”）和特发性PAH患者（“PAH”）的人肺动脉内皮细胞（HPAECs），并对每种细胞类型中的糖酵解活性、一氧化氮产生和eNOS的O-连接N-乙酰葡糖胺化进行了定量。我们的数据显示，与非PAH HPAECs相比，PAH HPAECs具有更高的葡萄糖摄取和糖酵解代谢产物，以及一氧化氮产生减少。然而，PAH HPAECs的eNOS O-连接N-乙酰葡糖胺化和O-连接N-乙酰葡糖胺化的底物UDP-GlcNAc较低。有趣的是，与雄性HPAECs相比，雌性HPAECs的葡萄糖摄取和eNOS O-连接N-乙酰葡糖胺化都更高。这些数据表明，尽管PAH中内皮糖酵解代谢发生了改变，但eNOS的O-连接N-乙酰葡糖胺化与一氧化氮减少无关。此外，来自雄性和雌性供体的HPAECs中葡萄糖代谢和蛋白质O-连接N-乙酰葡糖胺化的差异可能与PAH的性别差异有关。
