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.
Keywords: Alcoholic cardiomyopathy; Apoptosis; Autophagy; Cardiomyocyte; Cytochrome P450 epoxygenase 2J2; Epoxyeicosatrienoic acids; Ethanol.
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