Background

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.

Methods

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.

Results

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.

Conclusions

Glimepiride attenuates HF in mice in part by increasing EETs.

Clinical trial identifier: NCT03461107 (https://clinicaltrials.gov).

中文翻译：

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格列美脲是一种新型可溶性环氧化物水解酶抑制剂，通过增加环氧二十碳三烯酸来预防心力衰竭

背景

环氧二十碳三烯酸 (EET) 具有多种内源性保护作用，可被可溶性环氧化物水解酶 (sEH) 水解成活性较低的二羟基二十碳三烯酸 (DHET)。然而，与EETs或sEH相关的商业药物尚未进入临床使用。

方法

首先采用液相色谱-串联质谱法对316例心力衰竭(HF)患者的血浆EETs和DHETs浓度进行检测和定量。^{然后，在心肌细胞特异性 Ephx2 -/−}小鼠中引入横主动脉缩窄 (TAC) 诱导的心力衰竭。此外，还采用Western blot、实时PCR、荧光素酶报告基因、ChIP 检测来探索潜在机制。最后，设计、合成了多种 sEH 抑制剂，并在体外和体内进行了验证。

结果

心力衰竭患者血浆中 DHET/EET 的比率升高。同时，心力衰竭患者和小鼠心脏中sEH的表达上调，尤其是心肌细胞中。心肌细胞特异性 Ephx2 ^−/−小鼠改善了 TAC 诱导的心功能障碍。一致地，Ephx2 敲低通过增加体外 EET 来保护血管紧张素 II (AngII) 处理的心肌细胞。从机制上讲，AngII 可以增强转录因子 Krüppel 样因子 15 (KLF15) 的表达，从而上调 sEH。重要的是，格列美脲被认为是一种新型 sEH 抑制剂，它受益于心力衰竭期间 EET 的升高。

结论

格列美脲部分通过增加 EET 来减轻小鼠心力衰竭。

临床试验标识符： NCT03461107 ( https://clinicaltrials.gov )。