High-dose alcohol induces reactive oxygen species-mediated apoptosis via PKC-β/p66Shc in mouse primary cardiomyocytes

• High-dose alcohol induces ROS-mediated apoptosis in cardiomyocytes.
• p66Shc regulates alcohol-induced ROS generation and apoptosis in cardiomyocytes.
• Phosphorylated p66Shc induced by alcohol treatment interacts with Pin1 in cardiomyocytes.
• Alcohol causes mitochondrial membrane potential loss and cytochrome c release in cardiomyocytes via PKC-β/p66Shc signaling.

Cardiac dysfunction caused by excessive alcohol consumption is a specific disease, alcoholic cardiomyopathy (ACM). High-dose alcohol has been found to induce oxidation stress and apoptosis in cardiomyocytes, but the signaling link between alcohol-induced oxidation stress and apoptosis in cardiomyocytes remains to be elucidated. To address the issue, we exposed primary cardiomyocytes from neonatal mouse hearts to high doses of alcohol (50 mM, 100 mM, and 200 mM). We found that alcohol induced dose-dependent phosphorylation of p66shc, and reactive oxygen species (ROS) production increased in parallel with phosphorylation levels of p66shc. Exposure to alcohol also led to loss of mitochondrial membrane potential and cytochrome c release. Depletion of p66Shc and inhibition of protein kinase C-β (PKC-β) successfully reversed all the effects and suppressed alcohol-induced apoptosis in cardiomyocytes. Collectively, our study provides a molecular basis for signaling transduction of alcohol-induced oxidation stress and apoptosis of cardiomyocytes, which may facilitate the prevention and treatment of ACM.

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