Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany.
Curr Opin Lipidol. 2011 Oct;22(5):403-9. doi: 10.1097/MOL.0b013e32834a9790.
This review highlights recent advances in eicosanoid biology, especially linked to the cytochrome P450 (CYP)/soluble epoxide hydrolase (sEH) axis in vascular biology and disease.
Since the first reports that CYP-derived metabolites of arachidonic acid can elicit vascular smooth muscle hyperpolarization and relaxation, it has become clear that fatty acid epoxides and diols are important lipid signaling molecules. Targeting CYP epoxygenases in vivo is difficult as these enzymes are involved in the metabolism of many currently used clinical agents. However, targeting the sEH which metabolizes fatty acid epoxides to their corresponding diols is a highly effective way of manipulating levels of these lipid mediators in vivo. Indeed, sEH-/- mice are protected against the development of some forms of hypertension, and have altered adipocyte metabolism and insulin resistance, phenomena reproduced by selective sEH inhibitors.
Given that elevated epoxide levels have been linked with decreased blood pressure and inflammation in animal models, inhibitors of the sEH are currently being developed for the treatment of human hypertension and inflammation/atherosclerosis. This review focuses on outlining recent insights gained in the beneficial as well as the potentially adverse aspects of interfering with the CYP/sEH axis.
本综述强调了类二十烷酸生物学的最新进展，特别是与血管生物学和疾病中的细胞色素 P450（CYP）/可溶性环氧化物水解酶（sEH）轴相关的进展。
自首次报道花生四烯酸的 CYP 衍生代谢物可引起血管平滑肌超极化和松弛以来，已经清楚脂肪酸环氧化物和二醇是重要的脂质信号分子。由于这些酶参与许多目前使用的临床药物的代谢，因此体内靶向 CYP 加氧酶具有一定难度。然而，靶向代谢脂肪酸环氧化物为相应二醇的 sEH 是一种在体内有效操纵这些脂质介质水平的方法。事实上，sEH-/- 小鼠对某些形式的高血压的发展具有保护作用，并且改变了脂肪细胞代谢和胰岛素抵抗，这些现象可被选择性 sEH 抑制剂复制。
鉴于在动物模型中升高的环氧化物水平与血压降低和炎症有关，sEH 抑制剂目前正在被开发用于治疗人类高血压和炎症/动脉粥样硬化。本综述重点概述了干扰 CYP/sEH 轴的有益和潜在不利方面的最新见解。
