Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway.
Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway.
复制标题
DOI：
10.1097/fjc.0b013e31828165db
复制
发表时间：
2013-03
影响因子：
3
通讯作者：
Gauthier KM
中科院分区：
文献类型：
--
作者：
Campbell WB;Gauthier KM
内皮源性超极化因子 (EDHF) 通过促进剪切应力和内皮激动剂（如缓激肽和乙酰胆碱）的血管舒张来调节血管张力。 15(S)-羟基-11,12-环氧二十碳三烯酸 (15-H-11,12-EETA) 和 11(R),12(S),15(S)-三羟基二十碳三烯酸 (11,12,15-THETA) 是花生四烯酸代谢的 15-脂氧合酶 (15-LO) 途径的内皮代谢产物，是EDHF。 11,12,15-THETA 激活平滑肌细胞上的小电导钙激活钾通道，导致膜超极化和松弛。内皮细胞中 15-LO 的表达水平调节 15-LO/15-H-11,12-EETA/11,12,15-THETA 通路的活性及其对血管张力的贡献。其表达调节是通过转录、翻译和表观遗传机制实现的。缺氧、高胆固醇血症、动脉粥样硬化、贫血、雌激素、白细胞介素和可能的其他激素会增加 15-LO 的表达。 15-LO 的增加导致 15-H-11,12-EETA 和 11,12,15-THETA 的合成增加，膜超极化增加，内皮激动剂对松弛的贡献增强。因此，15-LO 途径代表了诱导型 EDHF 的第一个例子。除了 15-LO 代谢物外，许多化学物质已被鉴定为 EDHF，它们对血管张力的贡献因物种和血管床而异。多个 EDHF 的原因没有得到解释。然而，EDHF 作为组成型 EDHF 或诱导型 EDHF 发挥作用，可以解释 EDHF 活性需要化学和生物化学上不同的途径，以及物种和血管床之间 EDHF 的变化。这种新的 EDHF 分类为理解生理和病理条件下的 EDHF 活性提供了一个框架。
Endothelium-derived hyperpolarizing factors (EDHFs) regulate vascular tone by contributing to the vasorelaxations to shear stress and endothelial agonists such as bradykinin and acetylcholine. 15(S)-Hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA) and 11(R),12(S),15(S)-trihydroxyeicosatrienoic acid (11,12,15-THETA) are endothelial metabolites of the 15-lipoxygenase (15-LO) pathway of arachidonic acid metabolism and are EDHFs. 11,12,15-THETA activates small conductance, calcium-activated potassium channels on smooth muscle cells causing membrane hyperpolarization and relaxation. Expression levels of 15-LO in the endothelium regulate the activity of the 15-LO/15-H-11,12-EETA/11,12,15-THETA pathway and its contribution to vascular tone. Regulation of its expression is by transcriptional, translational and epigenetic mechanisms. Hypoxia, hypercholesterolemia, atherosclerosis, anemia, estrogen, interleukins and possibly other hormones increase 15-LO expression. An increase in 15-LO results in increased synthesis of 15-H-11,12-EETA and 11,12,15-THETA, increased membrane hyperpolarization and enhanced contribution to relaxation by endothelial agonists. Thus, the 15-LO pathway represents the first example of an inducible EDHF. In addition to 15-LO metabolites, a number of chemicals have been identified as EDHFs and their contributions to vascular tone vary with species and vascular bed. The reason for multiple EDHFs has evaded explanation. However, EDHFs functioning as constitutive EDHFs or inducible EDHFs may explain the need for chemically and biochemically distinct pathways for EDHF activity and the variation in EDHFs between species and vascular beds. This new EDHF classification provides a framework for understanding EDHF activity in physiological and pathological conditions.