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花生四烯酸细胞色素P450表氧化酶代谢物EETs的内源性心血管保护作用

何祚雯^1,2, 王贝³, 陈琛^1,2, 石泽琪², 汪道文^1,2,*

¹华中科技大学同济医学院附属同济医院心血管内科，武汉 430030；²心血管病遗传与分子机制湖北省重点实验室，武汉 430030；³华中科技大学同济医学院附属同济医院风湿内科，武汉 430030

摘要

花生四烯酸(arachidonic acid, AA)是生物体内最丰富的多不饱和脂肪酸，其代谢产物具有广泛的生物学活性。环氧二十碳三烯酸(epoxyeicosatrienoic acids, EETs)是AA经细胞色素P450表氧化酶(cytochrome P450 epoxygenase, CYP450)代谢产生的内源性小分子化合物，近20年的研究表明EETs具有广泛的心血管保护作用，是重要的内源性心血管保护因子。EETs不仅可以改善不同病因导致的心脏重构，抑制心肌肥厚，减轻不同因素导致的心肌损伤，还能明显改善上述病理过程所导致的血流动力学紊乱和心功能损害。在血管保护方面，最早的研究证明EETs是一种内皮来源的超极化因子，可以通过作用于内皮细胞和平滑肌上的钙离子敏感通道而发挥血管舒张作用，随后研究发现，EETs可能有更多非超极化效应而产生降压、改善冠状动脉血供、调节肺动脉压力等作用。此外，EETs还具有显著的内皮保护效应，可以抑制内皮细胞的炎症反应和黏附作用，抑制血小板聚集，促进纤溶和血管的新生。EETs还能改善主动脉重构，包括抑制动脉粥样硬化、主动脉外膜纤维化和主动脉钙化。EETs心血管保护作用的分子机制是多方面的，EETs可通过调控多个信号通路从而调节不同病理生理环节，是一种多靶点内源性心血管保护因子。因此研究EETs在心血管系统中的生理和病理生理作用有利于阐明心血管疾病的内源性保护机制，为心血管疾病的防治提供新策略。本文综述了EETs的内源性心血管保护作用和机制，以期为该领域的转化研究提供新的思路。

关键词： 花生四烯酸; 细胞色素P450表氧化酶; 环氧二十碳三烯酸; 心肌保护作用; 血管稳态调节; 分子机制

分类号：R54; Q547

Endogenous protective effects of arachidonic acid epoxygenase metabolites, epoxyeicosatrienoic acids, in cardiovascular system

HE Zuo-Wen^1,2, WANG Bei³, CHEN Chen^1,2, SHI Ze-Qi², WANG Dao-Wen^1,2,*

¹Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Huazhong University of Science and Technology, Wuhan 430030, China；²Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China；³Division of Rheumatology and Immunology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Abstract

The morbidity and mortality of cardiovascular diseases are increasing annually, which is one of the primary causes of human death. Recent studies have shown that epoxyeicosatrienoic acids (EETs), endogenous metabolites of arachidonic acid (AA) via CYP450 epoxygenase, possess a spectrum of protective properties in cardiovascular system. EETs not only alleviate cardiac remodeling and injury in different pathological models, but also improve subsequent hemodynamic disturbances and cardiac dysfunction. Meanwhile, various studies have demonstrated that EETs, as endothelial-derived hyperpolarizing factors, regulate vascular tone by activating various ion channels on endothelium and smooth muscle, which in turn can lower blood pressure, improve coronary blood flow and regulate pulmonary artery pressure. In addition, EETs are protective in endothelium, including inhibiting inflammation and adhesion of endothelial cells, attenuating platelet aggregation, promoting fibrinolysis and revascularization. EETs can also prevent aortic remodeling, including attenuating atherosclerosis, adventitial remodeling, and aortic calcification. Therefore, it is clinically important to study the physiological and pathophysiological effects of EETs in the cardiovascular system to further elucidate the mechanisms, as well as provide new strategy for the prevention and treatment of cardiovascular diseases. This review summarizes the endogenous cardioprotective effects and mechanisms of EETs in order to provide a new insight for research in this field.

Key words: arachidonic acid; CYP450 epoxygenase; epoxyeicosatrienoic acids; cardiac protection; vascular homeostasis regulation; molecular mechanism

收稿日期：2021-02-05　　录用日期：2021-03-29

通讯作者：汪道文　　E-mail: dwwang@tjh.tjmu.edu.cn

DOI: 10.13294/j.aps.2021.0053

引用本文：

何祚雯, 王贝, 陈琛, 石泽琪, 汪道文. 花生四烯酸细胞色素P450表氧化酶代谢物EETs的内源性心血管保护作用[J]. 生理学报 2021; 73 (4): 617-630.

HE Zuo-Wen, WANG Bei, CHEN Chen, SHI Ze-Qi, WANG Dao-Wen. Endogenous protective effects of arachidonic acid epoxygenase metabolites, epoxyeicosatrienoic acids, in cardiovascular system. Acta Physiol Sin 2021; 73 (4): 617-630 (in Chinese with English abstract).