Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Chronic Ethanol-Induced Cardiac Fibrosis by Restoring Autophagic Flux.
Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Chronic Ethanol-Induced Cardiac Fibrosis by Restoring Autophagic Flux.
复制标题
可溶性环氧化物水解酶的药理抑制通过恢复自噬通量改善慢性乙醇诱导的心脏纤维化。
DOI：
10.1111/acer.13847
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Wang Dao Wen
中科院分区：
文献类型：
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作者：
Zhou Chi;Huang Jin;Li Qing;Zhan Chenao;He Ying;Liu Jinyan;Wen Zheng;Wang Dao Wen
背景：长期饮酒可导致心肌收缩功能障碍和扩张型心肌病，心脏纤维化是这些酒精损伤的后果。可溶性环氧化物水解酶（sEH）可将环氧二碳三烯酸（eet）水解为生物活性较低的二醇，eet具有保护心脏的特性。然而，sEH抑制对乙醇（EtOH）诱导的心脏纤维化的影响尚不清楚。方法本研究旨在探讨sEH抑制在慢性EtOH饲养诱导的心脏纤维化中的作用和潜在机制。C57BL/6J小鼠饲喂4% Lieber‐DeCarli EtOH饲料8周，并在整个实验期间给予sEH抑制剂1‐三氟甲氧基苯基‐3‐（1‐丙基哌啶‐4‐基）尿素（TPPU）。结果结果表明，长期摄取EtOH可导致心脏扩张、胶原沉积和自噬体积累，而TPPU可改善这些作用。在体外，用EtOH处理原代心脏成纤维细胞（CF）导致CF活化，包括α平滑肌肌动蛋白过表达、胶原合成和细胞迁移。此外，EtOH干扰CF自噬通量，LC3 II/I比值和SQSTM1表达增加，自噬体积累增强。TPPU处理可阻止EtOH诱导的CF活化，并通过抑制mTOR活化来恢复受损的自噬通量。综上所述，这些发现表明，sEH药物抑制可能是治疗EtOH诱导的心脏纤维化的一种独特的治疗策略。
BackgroundChronic drinking leads to myocardial contractile dysfunction and dilated cardiomyopathy, and cardiac fibrosis is a consequence of these alcoholic injuries. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) to less bioactive diols, and EETs have cardioprotective properties. However, the effects of sEH inhibition in ethanol (EtOH)‐induced cardiac fibrosis are unknown.MethodsThis study was designed to investigate the role and underlying mechanisms of sEH inhibition in chronic EtOH feeding‐induced cardiac fibrosis. C57BL/6J mice were fed a 4% Lieber‐DeCarli EtOH diet for 8 weeks, and the sEH inhibitor 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl) urea (TPPU) was administered throughout the experimental period.ResultsThe results showed that chronic EtOH intake led to cardiac dilatation, collagen deposition, and autophagosome accumulation, while TPPU administration ameliorated these effects. In vitro, treating primary cardiac fibroblasts (CFs) with EtOH resulted in CF activation, including alpha smooth muscle actin overexpression, collagen synthesis, and cell migration. Moreover, EtOH disturbed CF autophagic flux, as evidenced by the increased LC3 II/I ratio and SQSTM1 expression, and by the enhanced autophagosome accumulation. TPPU treatment prevented the activation of CF induced by EtOH and restored the impaired autophagic flux by suppressing mTOR activation.ConclusionsTaken together, these findings suggest that sEH pharmacological inhibition may be a unique therapeutic strategy for treating EtOH‐induced cardiac fibrosis.