Abstract
Endothelial dysfunction is a key early link in the pathogenesis of atherosclerosis, and the accumulation of senescent vascular endothelial cells causes endothelial dysfunction. Phosphoenolpyruvate (PEP), which is a high-energy glycolytic intermediate, protects against ischemia-reperfusion injury in isolated rat lung, heart, and liver tissue by quickly providing ATP. However, it was reported that serum PEP concentrations are 13-fold higher in healthy elderly compare to the young. Unlike that of other cell types, the energy required for the physiological function of endothelial cells is mainly derived from glycolysis. Recently, it is unclear whether circulating accumulation of PEP affects endothelial cell function. In this study, we found for the first time that 50-250 μM of PEP significantly promoted THP-1 monocyte adhesion to human umbilical vein endothelial cells (HUVECs) through increased expression of vascular endothelial adhesion factor 1 (VCAM1) and intercellular adhesion factor 1 (ICAM1) in HUVECs. Meanwhile, 50-250 μM of PEP decreased the expression of endothelial nitric oxide synthase (eNOS) and cellular level of nitric oxide (NO) in HUVECs. Moreover, PEP increased levels of ROS, enhanced the numbers of SA-β-Gal-positive cells and upregulated the expression of cell cycle inhibitors such as p21, p16 and the phosphorylation level of p53 on Ser15, and the expression of proinflammatory factors including TNF-α, IL-1β, IL-6, IL-8, IL-18 and MCP-1 in HUVECs. Furthermore, PEP increased both oxygen consumption rate (OCR) and glycolysis rate, and was accompanied by reduced NAD+/NADH ratios and enhanced phosphorylation levels of AMPKα (Thr172), p38 MAPK (T180/Y182) and NF-κB p65 (Ser536) in HUVECs. Notably, PEP had no significant effect on hepG2 cells. In conclusion, these results demonstrated that PEP induced dysfunction and senescence in vascular endothelial cells through stimulation of metabolic reprogramming.
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Data availability statement
The data that support the findings of this study are available from the corresponding author, [WT], upon reasonable request.
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Funding
This work was supported by the Beijing Natural Science Foundation (7212086, 7232141), the National Key R&D Program of China (2021YFE0114200) and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (grant no. 2021-I2M-1–050).
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Conceptualization, Weiqing Tang and Jian Li; Data curation, Tong An and Weiqing Tang; Formal analysis, Tong An and Weiqing Tang; Funding acquisition, Weiqing Tang and Jian Li; Investigation, Weiqing Tang; Methodology, Tong An, Xiaoyi Zhang, Xin Gao, Xiyue Zhang, Tao Shen, Hongxia Li, Lin Dou, Xiuqing Huang, Yong Man, Guoping Li and Weiqing Tang; Project administration, Weiqing Tang and Jian Li; Resources, Weiqing Tang and Jian Li; Software, Tong An, Xiaoyi Zhang and Weiqing Tang; Supervision, Weiqing Tang and Jian Li; Validation, Tong An; Visualization, Tong An and Weiqing Tang; Writing – original draft, Tong An; Writing – review & editing, Weiqing Tang and Jian Li.
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An, T., Zhang, X., Gao, X. et al. Phosphoenolpyruvate induces endothelial dysfunction and cell senescence through stimulation of metabolic reprogramming. J Bioenerg Biomembr 55, 103–114 (2023). https://doi.org/10.1007/s10863-023-09965-8
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DOI: https://doi.org/10.1007/s10863-023-09965-8