Iwate Biotechnology Research Center, 22-174-4 Narita, Kitakami, Iwate 024-0003, Japan.
Nutrients. 2017 Sep 11;9(9):1001. doi: 10.3390/nu9091001.
5-hydroxyeicosatetraenoic acid (5-HETE) and 5-hydroxyeicosapentaenoic acid (5-HEPE) are major metabolites produced by 5-lipoxygenase (5-LOX) from arachidonic acid (AA) and eicosapentaenoic acid (EPA). Effects of hydroxides on endothelial cells are unclear, although 5-LOX is known to increase at arteriosclerotic lesions. To investigate the effects of hydroxides on human umbilical vein endothelial cells (HUVECs), the cells were treated with 50 μM each of AA, EPA, 5-HETE, and 5-HEPE. Treatment of HUVECs with 5-HETE and 5-HEPE, rather than with AA and EPA, increased the nuclear translocation of NF-E2 related factor 2 (Nrf2) and upregulated the expression of heme oxygenase-1 and cystine/glutamate transporter regulated by Nrf2. Reactive oxygen species (ROS) generation was markedly elevated in HUVECs after treatment with 5-HETE and 5-HEPE, and the pretreatment with α-tocopherol abrogated ROS levels similar to those in the vehicle control. However, ROS generation was independent of Nrf2 activation induced by 5-HETE and 5-HEPE. 5-HETE was converted to 5-oxo-eicosatetraenoic acid (5-oxo-ETE) in HUVECs, and 5-oxo-ETE increased Nrf2 activation. These results suggest that 5-HETE works as an Nrf2 activator through the metabolite 5-oxo-ETE in HUVECs. Similarly, 5-HEPE works in the same way, because 5-HEPE is metabolized to 5-oxo-eicosapentaenoic acid through the same pathway as that for 5-HETE.
5-羟二十碳四烯酸（5-HETE）和 5-羟二十碳五烯酸（5-HEPE）是花生四烯酸（AA）和二十碳五烯酸（EPA）经 5-脂氧合酶（5-LOX）生成的主要代谢产物。尽管已知 5-LOX 在动脉粥样硬化病变处增加，但羟基对血管内皮细胞的影响尚不清楚。为了研究羟基对人脐静脉内皮细胞（HUVEC）的影响，用 50μM 的 AA、EPA、5-HETE 和 5-HEPE 分别处理 HUVEC。与 AA 和 EPA 相比，5-HETE 和 5-HEPE 处理 HUVEC 增加了核转录因子 Nrf2 的核易位，并上调了血红素加氧酶-1 和 Nrf2 调节的胱氨酸/谷氨酸转运体的表达。与载体对照组相比，5-HETE 和 5-HEPE 处理后 HUVEC 中活性氧（ROS）的生成显著增加，而 α-生育酚预处理可消除 ROS 水平，与载体对照组相似。然而，ROS 的生成与 5-HETE 和 5-HEPE 诱导的 Nrf2 激活无关。5-HETE 在 HUVEC 中转化为 5-氧代二十碳四烯酸（5-oxo-ETE），而 5-oxo-ETE 增加了 Nrf2 的激活。这些结果表明，5-HETE 通过 HUVEC 中的代谢产物 5-oxo-ETE 作为 Nrf2 激活剂发挥作用。同样，5-HEPE 通过与 5-HETE 相同的途径代谢为 5-oxo-二十碳五烯酸，因此也以同样的方式发挥作用。
