Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1788-94. doi: 10.1161/ATVBAHA.113.301300. Epub 2013 May 30.
In addition to an extensively characterized role of high-density lipoprotein (HDL) in reverse cholesterol transport, bioactive lipids bound to HDL can also exert diverse vascular effects. Despite this, integration of HDL action in the vasculature with pathways that metabolize HDL and release bioactive lipids has been much less explored. The effects of HDL on endothelial cells are mediated in part by HDL-associated sphingosine 1-phosphate (S1P), which binds to S1P1 receptors and promotes activation of endothelial NO synthase (eNOS) and the kinase Akt. In these studies, we characterized the role of endothelial lipase (EL) in the control of endothelial signaling and biology, including those mediated by HDL-associated S1P.
HDL-induced angiogenesis in aortic rings from EL-deficient (EL(-/-)) mice was markedly decreased compared with wild-type controls. In cultured endothelial cells, small interfering RNA-mediated knockdown of EL abrogated HDL-promoted endothelial cell migration and tube formation. Small interfering RNA-mediated EL knockdown also attenuated HDL-induced phosphorylation of eNOS(1179) and Akt(473). S1P stimulation restored HDL-induced endothelial migration and Akt/eNOS phosphorylation that had been blocked by small interfering RNA-mediated EL knockdown. HDL-induced endothelial cell migration and Akt/eNOS phosphorylation were completely inhibited by the S1P1 antagonist W146 but not by the S1P3 antagonist CAY10444.
EL is a critical determinant of the effects of HDL on S1P-mediated vascular responses and acts on HDL to promote activation of S1P1, leading to Akt/eNOS phosphorylation and subsequent endothelial migration and angiogenesis. The role of EL in HDL-associated S1P effects provides new insights into EL action, the responses seen through EL and HDL interaction, and S1P signaling.
除了高密度脂蛋白（HDL）在胆固醇逆转运中广泛作用之外，与 HDL 结合的生物活性脂质也能发挥多种血管作用。尽管如此，HDL 在血管中的作用与代谢 HDL 并释放生物活性脂质的途径的整合研究得要少得多。HDL 对内皮细胞的作用部分是通过与 HDL 相关的鞘氨醇 1-磷酸（S1P）介导的，S1P 与 S1P1 受体结合，促进内皮型一氧化氮合酶（eNOS）和蛋白激酶 B（Akt）的激活。在这些研究中，我们研究了内皮脂肪酶（EL）在控制内皮信号和生物学中的作用，包括由与 HDL 相关的 S1P 介导的作用。
与野生型对照相比，EL 缺陷（EL（-/-））小鼠主动脉环中 HDL 诱导的血管生成明显减少。在培养的内皮细胞中，EL 的小干扰 RNA 介导的敲低消除了 HDL 促进的内皮细胞迁移和管状形成。EL 的小干扰 RNA 介导的敲低也减弱了 HDL 诱导的 eNOS（1179）和 Akt（473）磷酸化。S1P 刺激恢复了被小干扰 RNA 介导的 EL 敲低阻断的 HDL 诱导的内皮细胞迁移和 Akt/eNOS 磷酸化。S1P1 拮抗剂 W146 完全抑制了 HDL 诱导的内皮细胞迁移和 Akt/eNOS 磷酸化，但 S1P3 拮抗剂 CAY10444 则没有。
EL 是 HDL 对 S1P 介导的血管反应影响的关键决定因素，它作用于 HDL 以促进 S1P1 的激活，导致 Akt/eNOS 磷酸化，随后内皮细胞迁移和血管生成。EL 在与 HDL 相关的 S1P 作用中的作用为 EL 作用、通过 EL 和 HDL 相互作用观察到的反应以及 S1P 信号提供了新的见解。
