Soluble epoxide hydrolase deficiency rescues heart failure with preserved ejection fraction by targeting cytochrome P450 2E1
文献类型：期刊论文
| 作者 | Zhang, Min2,3,4; Chen, Chen2,3; Liu, Xinxing4; Zhou, Zhou2,3; Li, Gen2,3; Jiang, Xiangrui1; Shen, Jingshan1; Jiang, Hualiang1; Wen, Zheng2,3; Liu, Yan4 |
| 刊名 | JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
 |
| 出版日期 | 2026 |
| 卷号 | 210页码:98-108 |
| 关键词 | Soluble epoxide hydrolase Desuccinylation Epoxyeicosatrienoic acids Heart failure with preserved ejection fraction |
| ISSN号 | 0022-2828 |
| DOI | 10.1016/j.yjmcc.2025.11.005 |
| 英文摘要 | Background: Our prior clinical studies established a positive correlation between sEH activity and mortality in heart failure with preserved ejection fraction (HFpEF), the pathophysiological role of the sEH/EET axis in metabolic stress (obesity and metabolic syndrome) and mechanical stress (hypertension)-induced HFpEF remains unknown. Methods: We elucidated the function and mechanism of sEH and EETs in 'two-hit' (high-fat diet and inhibition of constitutive nitric oxide synthase using N omega-nitrol-arginine methyl ester) HFpEF animal model. Langendorff system was applied to isolate cardiomyocytes from HFpEF mice. Recombinant adeno-associated virus type 9 was used to deliver cytochrome P450 2E1 (CYP2E1) to cardiac-specific knockout sEH HFpEF mice through the tail vein. Results: sEH activity and expression were upregulated, while EETs levels were reduced in the hearts and isolated cardiomyocytes from HFpEF mice or cardiomyocyte cell lines pretreated with palmitate acid and N omega-nitrolarginine methyl ester. Desuccinylation, a posttranslational modification of sEH (K)191, maintained the activity of sEH in HFpEF. Genetic or pharmacological inhibition of the sEH restored the levels of EETs and ameliorated HFpEF phenotype with significantly improved diastolic dysfunction and cardiac remodeling. Mechanically, sEH inhibitors (sEHIs) targeted CYP2E1, a crucial CYP450 enzyme, to inhibit reactive oxygen species (ROS) and fatty acid uptake. Overexpressing CYP2E1 abolished the protective effects of sEH inhibition in vivo. Conclusions: These findings confirmed sEH as a therapeutic target in metabolic stress and mechanical stress-induced HFpEF mice model via the cardioprotective effects of EETs, which were mediated partially by targeting CYP2E1, suggesting the development of therapeutic strategies for patients with HFpEF. |
| WOS关键词 | EPOXYEICOSATRIENOIC ACIDS ; DIABETIC CARDIOMYOPATHY ; SYSTOLIC FUNCTION ; ACTIVATION ; OVEREXPRESSION ; HYPERTROPHY ; METABOLITES ; PREVALENCE ; INDUCTION ; OUTCOMES |
| 资助项目 | Natural Science Foundation of China[82000383] ; Natural Science Foundation of China[82460076] ; Natural Science Foundation of China[82070395] ; Fundamental Research Funds for the Central Universities[2015ZDTD044] |
| WOS研究方向 | Cardiovascular System & Cardiology ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001622659200001 |
| 出版者 | ELSEVIER SCI LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322046]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Wen, Zheng; Liu, Yan; Wang, Dao Wen |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 2.Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Wuhan 430030, Peoples R China 3.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Cardiol,Dept Internal Med, Wuhan 430030, Peoples R China 4.Hainan Med Univ, Hainan Acad Med Sci, Sch Pharm, Haikou 571199, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Min,Chen, Chen,Liu, Xinxing,et al. Soluble epoxide hydrolase deficiency rescues heart failure with preserved ejection fraction by targeting cytochrome P450 2E1[J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY,2026,210:98-108. |
| APA | Zhang, Min.,Chen, Chen.,Liu, Xinxing.,Zhou, Zhou.,Li, Gen.,...&Wang, Dao Wen.(2026).Soluble epoxide hydrolase deficiency rescues heart failure with preserved ejection fraction by targeting cytochrome P450 2E1.JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY,210,98-108. |
| MLA | Zhang, Min,et al."Soluble epoxide hydrolase deficiency rescues heart failure with preserved ejection fraction by targeting cytochrome P450 2E1".JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 210(2026):98-108. |
入库方式： OAI收割
来源：上海药物研究所
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