Quiescent Endothelial Cells Upregulate Fatty Acid (β-Oxidation for Vasculoprotection via Redox Homeostasis
Quiescent Endothelial Cells Upregulate Fatty Acid (β-Oxidation for Vasculoprotection via Redox Homeostasis
复制标题
静止内皮细胞上调脂肪酸（β-氧化作用，通过氧化还原稳态实现血管保护）
DOI：
10.1016/j.cmet.2018.07.016
复制
发表时间：
2018-12-04
期刊：
影响因子：
29
通讯作者：
Carmeliet, Peter
中科院分区：
文献类型：
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作者：
Kalucka, Joanna;Bierhansl, Laura;Carmeliet, Peter
人们对静态内皮细胞（QEC）的代谢知之甚少。尽管如此，当 QEC 功能失调时，它会导致多种疾病。之前，我们证明增殖内皮细胞 (PEC) 使用脂肪酸 β-氧化 (FAO) 进行 dNTP 从头合成。我们现在报告说，QEC 不是代谢低下的，但对 FAO 的上调作用比 PEC 高 3 倍以上，不是为了支持生物质或能源生产，而是通过 NADPH 再生维持三羧酸循环以实现氧化还原稳态。因此，CPT1A(Delta EC)小鼠中FAO控制的CPT1A的内皮缺失通过增加内皮氧化应激而促进EC功能障碍(白细胞浸润、屏障破坏)，使CPT1A(Delta EC)小鼠更容易受到LPS和炎症性肠病的影响。从机制上讲，Notch1 协调使用FAO 来实现QEC 中的氧化还原平衡。补充乙酸盐（代谢为乙酰辅酶 A）可以恢复 CPT1A(Delta EC) 小鼠的内皮静止状态并对抗氧化应激介导的 EC 功能障碍，从而提供治疗机会。因此，QEC 使用FAO 来保护血管，防止氧化应激倾向的暴露。
Little is known about the metabolism of quiescent endothelial cells (QECs). Nonetheless, when dysfunctional, QECs contribute to multiple diseases. Previously, we demonstrated that proliferating endothelial cells (PECs) use fatty acid beta-oxidation (FAO) for de novo dNTP synthesis. We report now that QECs are not hypometabolic, but upregulate FAO >3-fold higher than PECs, not to support biomass or energy production but to sustain the tricarboxylic acid cycle for redox homeostasis through NADPH regeneration. Hence, endothelial loss of FAO-controlling CPT1A in CPT1A(Delta EC) mice promotes EC dysfunction (leukocyte infiltration, barrier disruption) by increasing endothelial oxidative stress, rendering CPT1A(Delta EC) mice more susceptible to LPS and inflammatory bowel disease. Mechanistically, Notch1 orchestrates the use of FAO for redox balance in QECs. Supplementation of acetate (metabolized to acetyl-coenzyme A) restores endothelial quiescence and counters oxidative stress-mediated EC dysfunction in CPT1A(Delta EC) mice, offering therapeutic opportunities. Thus, QECs use FAO for vasculoprotection against oxidative stress-prone exposure.