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Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids

文献类型：期刊论文

作者Zhao, Chengcheng3,4; Jiang, Xiangrui1,2; Peng, Liyuan3,4; Zhang, Yan2; Li, Huihui3,4; Zhang, Qiumeng2; Wang, Yinhui3,4; Yang, Feipu2; Wu, Junfang3,4; Wen, Zheng3,4
刊名JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
出版日期2023-12-01
卷号185页码:13-25
关键词Heart failure Hypertrophy Epoxyeicosatrienoic acids Soluble epoxide hydrolase
ISSN号0022-2828
DOI10.1016/j.yjmcc.2023.10.009
通讯作者Jiang, Xiangrui(jiangxiangrui@simm.ac.cn) ; Shen, Jingshan(shenjingshan@simm.ac.cn) ; Chen, Chen(chenchen@tjh.tjmu.edu.cn) ; Wang, Dao Wen(dwwang@tjh.tjmu.edu.cn)
英文摘要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 Kruppel-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).
WOS关键词SINGLE-CELL RECONSTRUCTION ; CARDIAC-HYPERTROPHY ; REVEALS ; EICOSANOIDS ; ISCHEMIA ; RECOVERY ; THERAPY ; CYP2J2
资助项目National Key Research and Development Program of China[2022YFC3400700] ; Na-tional Natural Science Foundation of China[U22A20266] ; Na-tional Natural Science Foundation of China[81790624] ; Na-tional Natural Science Foundation of China[91839302] ; Na-tional Natural Science Foundation of China[82270363] ; Na-tional Natural Science Foundation of China[81900341]
WOS研究方向Cardiovascular System & Cardiology ; Cell Biology
语种英语
WOS记录号WOS:001101836900001
出版者ELSEVIER SCI LTD
源URL[http://119.78.100.183/handle/2S10ELR8/308179]  
专题新药研究国家重点实验室
通讯作者Jiang, Xiangrui; Shen, Jingshan; Chen, Chen; Wang, Dao Wen
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Wuhan, Peoples R China
4.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Cardiol, Wuhan, Peoples R China
推荐引用方式
GB/T 7714		 Zhao, Chengcheng,Jiang, Xiangrui,Peng, Liyuan,et al. Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids[J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY,2023,185:13-25.
APA Zhao, Chengcheng.,Jiang, Xiangrui.,Peng, Liyuan.,Zhang, Yan.,Li, Huihui.,...&Wang, Dao Wen.(2023).Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids.JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY,185,13-25.
MLA Zhao, Chengcheng,et al."Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids".JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 185(2023):13-25.

入库方式： OAI收割

来源：上海药物研究所

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