CYP2J2-derived EETs attenuated ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis.
CYP2J2-derived EETs attenuated ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis.
复制标题
CYP2J2 衍生的 EET 通过诱导自噬和减少细胞凋亡来减轻乙醇诱导的心肌功能障碍。
DOI：
10.1016/j.freeradbiomed.2018.02.009
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发表时间：
2018
影响因子：
7.4
通讯作者：
Wang Dao Wen
中科院分区：
文献类型：
--
作者：
Zhou Chi;Huang Jin;Li Qing;Zhan Chenao;Xu Xizhen;Zhang Xu;Ai Ding;Zhu Yi;Wen Zheng;Wang Dao Wen
慢性过量饮酒导致心肌收缩功能障碍和扩张型心肌病，其中乙醇毒性起重要作用。细胞色素P450 （CYP）环氧合酶代谢花生四烯酸形成环氧二碳三烯酸（EETs），其在心血管系统中发挥有益作用，但其在酒精性心肌病中的作用尚不清楚。本研究旨在探讨CYP2J2基因传递对乙醇诱导心肌功能障碍的影响及其机制，重点关注自噬和细胞凋亡。C57BL/6 J小鼠灌胃4% Lieber-DeCarli乙醇液体饲粮8周后，经尾静脉注射rAAV9-CYP2J2。使用超声心动图、血流动力学测量和心脏组织学评估心功能。结果表明，慢性乙醇摄入可导致心脏扩张、收缩功能障碍、心肌细胞肥大、氧化应激和心肌细胞凋亡，而CYP2J2过表达可改善这些影响。此外，慢性乙醇消耗触发心肌自噬体形成，但通过破坏自噬体与溶酶体的融合而损害自噬通量，LC3 II/I、Beclin-1和SQSTM1水平升高，但LAMP-2表达降低。有趣的是，rAAV9-CYP2J2治疗通过恢复酒精性心肌的自噬通量来发挥心脏保护作用。同样，外源性11,12- eet的加入也能显著恢复乙醇诱导的新生大鼠心肌细胞自噬通量损伤，并抑制细胞凋亡，这两种损伤都是通过AMPK/mTOR信号通路介导的。综上所述，我们的数据表明，cyp2j2衍生的eet通过诱导自噬和减少细胞凋亡来减轻乙醇诱导的心肌功能障碍。
Chronic excessive drinking leads to myocardial contractile dysfunction and dilated cardiomyopathy, where ethanol toxicity plays an essential role. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the cardiovascular system, but their role in alcoholic cardiomyopathy is elusive. This study was designed to evaluate the effects and mechanisms of CYP2J2 gene delivery on ethanol-induced myocardial dysfunction with focus on autophagy and apoptosis. C57BL/6 J mice were challenged with a 4% Lieber-DeCarli ethanol liquid diet for 8 weeks, before which rAAV9-CYP2J2 was injected via the tail vein. Cardiac function was assessed using echocardiography, hemodynamic measurement, and cardiac histology. The results showed that chronic ethanol intake led to cardiac dilation, contractile dysfunction, cardiomyocyte hypertrophy, oxidative stress, and cardiomyocyte apoptosis, while CYP2J2 overexpression ameliorated these effects. Additionally, chronic ethanol consumption triggered myocardial autophagosome formation, but impaired autophagic flux via disrupting autophagosome-lysosome fusion, as evidenced by increased LC3 II/I, Beclin-1 and SQSTM1 levels, but reduced LAMP-2 expression. Interestingly, rAAV9-CYP2J2 treatment exerted cardioprotection via restoring autophagic flux in the alcoholic myocardium. Similarly, exogenous 11,12-EET addition significantly restored ethanol-induced neonatal rat cardiomyocyte autophagic flux impairment and inhibited apoptosis, both of which were mediated by AMPK/mTOR signaling pathway in vitro. In conclusion, our data suggest that CYP2J2-derived EETs attenuate ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis.