Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, China.
J Mol Cell Cardiol. 2023 Dec;185:13-25. doi: 10.1016/j.yjmcc.2023.10.009. Epub 2023 Oct 21.
Epoxyeicosatrienoic acids (EETs), which exert multiple endogenous protective effects, are hydrolyzed into less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). However, commercial drugs related to EETs or sEH are not yet in clinical use.
Firstly, the plasma concentration of EETs and DHETs of 316 patients with heart failure (HF) were detected and quantitated by liquid chromatography-tandem mass spectrometry. Then, transverse aortic constriction (TAC)-induced HF was introduced in cardiomyocyte-specific Ephx2 mice. Moreover, Western blot, real-time PCR, luciferase reporter, ChIP assays were employed to explore the underlying mechanism. Finally, multiple sEH inhibitors were designed, synthesized, and validated in vitro and in vivo.
The ratios of DHETs/EETs were increased in the plasma from patients with HF. Meanwhile, the expression of sEH was upregulated in the heart of patients and mice with HF, especially in cardiomyocytes. Cardiomyocyte-specific Ephx2 mice ameliorated cardiac dysfunction induced by TAC. Consistently, Ephx2 knockdown protected Angiotensin II (AngII)-treated cardiomyocytes via increasing EETs in vitro. Mechanistically, AngII could enhance the expression of transcript factor Krüppel-like factor 15 (KLF15), which in turn upregulated sEH. Importantly, glimepiride was identified as a novel sEH inhibitor, which benefited from the elevated EETs during HF.
Glimepiride attenuates HF in mice in part by increasing EETs.
NCT03461107 (https://clinicaltrials.gov).
环氧二十碳三烯酸（EETs）具有多种内源性保护作用，可被可溶性环氧化物水解酶（sEH）水解为活性较低的二羟二十碳三烯酸（DHETs）。然而，与 EETs 或 sEH 相关的商业药物尚未在临床中使用。
首先，通过液相色谱-串联质谱法检测并定量了 316 例心力衰竭（HF）患者的血浆 EETs 和 DHETs 浓度。然后，在心肌细胞特异性 Ephx2 小鼠中引入了主动脉缩窄（TAC）诱导的 HF。此外，还采用 Western blot、实时 PCR、荧光素酶报告基因、ChIP 检测等方法来探讨潜在的机制。最后，设计、合成并在体外和体内验证了多种 sEH 抑制剂。
HF 患者血浆中的 DHETs/EETs 比值增加。同时，HF 患者和小鼠的心脏中 sEH 表达上调，尤其是在心肌细胞中。心肌细胞特异性 Ephx2 小鼠改善了 TAC 诱导的心脏功能障碍。同样，Ephx2 敲低通过增加体外 AngII 处理的心肌细胞中的 EETs 来保护 AngII 处理的心肌细胞。机制上，AngII 可以增强转录因子 Krüppel-like factor 15（KLF15）的表达，从而上调 sEH。重要的是，格列美脲被鉴定为一种新型的 sEH 抑制剂，它在 HF 期间通过增加 EETs 而受益。
格列美脲通过增加 EETs 在一定程度上减轻了小鼠的 HF。
NCT03461107（https://clinicaltrials.gov）。
