CYP2J2-derived EETs attenuated ethanol-induced myocardial dysfunction through inducing autophagy and reducing...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Toxicology

Background:

• Chronic excessive alcohol consumption causes myocardial contractile dysfunction and dilated cardiomyopathy.
• Ethanol toxicity is a key factor, but the role of epoxyeicosatrienoic acids (EETs) in alcoholic cardiomyopathy remains unclear.
• Cytochrome P450 (CYP) epoxygenases produce EETs, which have protective cardiovascular effects.

Purpose of the Study:

• To investigate the effects of CYP2J2 gene delivery on ethanol-induced myocardial dysfunction.
• To elucidate the mechanisms involving autophagy and apoptosis in alcoholic cardiomyopathy.
• To evaluate the cardioprotective potential of CYP2J2-derived EETs.

Main Methods:

• Adeno-associated virus serotype 9 (rAAV9)-mediated CYP2J2 gene delivery in C57BL/6J mice fed an ethanol diet for 8 weeks.
• Assessment of cardiac function via echocardiography, hemodynamic measurements, and cardiac histology.
• In vitro studies using neonatal rat cardiomyocytes treated with ethanol and 11,12-EET, with analysis of autophagy and apoptosis markers.

Main Results:

• Chronic ethanol intake induced cardiac dilation, contractile dysfunction, cardiomyocyte hypertrophy, oxidative stress, and apoptosis.
• CYP2J2 overexpression ameliorated ethanol-induced cardiac damage.
• Ethanol impaired autophagic flux by disrupting autophagosome-lysosome fusion, which was restored by rAAV9-CYP2J2 treatment.
• Exogenous 11,12-EET addition restored autophagic flux and inhibited apoptosis in vitro, mediated by the AMPK/mTOR pathway.

Conclusions:

• CYP2J2-derived EETs attenuate ethanol-induced myocardial dysfunction.
• Cardioprotection is achieved by restoring autophagic flux and reducing cardiomyocyte apoptosis.
• CYP2J2 gene therapy represents a potential strategy for treating alcoholic cardiomyopathy.