Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Chronic Ethanol-induced Cardiac Fibrosis by Restoring Autophagic Flux

BACKGROUND: Chronic 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 to less bioactive diols, and epoxyeicosatrienoic acids have cardioprotective properties. However, the effects of sEH inhibition in ethanol-induced cardiac fibrosis are unknown. METHODS AND RESULTS: This study was designed to investigate the role and underlying mechanisms of sEH inhibition in chronic ethanol feeding-induced cardiac fibrosis. C57BL/6J mice were fed a 4% Lieber-DeCarli ethanol diet for 8 weeks, and the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) was administered throughout the experimental period. The results showed that chronic ethanol intake led to cardiac dilatation, collagen deposition and autophagosome accumulation, while TPPU administration ameliorated these effects. In vitro, treating primary cardiac fibroblasts with ethanol resulted in cardiac fibroblast activation, including α-SMA overexpression, collagen synthesis, and cell migration. Moreover, ethanol disturbed cardiac fibroblast 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 cardiac fibroblast induced by ethanol and restored the impaired autophagic flux by suppressing mTOR activation. CONCLUSIONS: Taken together, these findings suggest that sEH pharmacological inhibition may be a unique therapeutic strategy for treating ethanol-induced cardiac fibrosis.