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

[Display omitted] •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 pote...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2015-01, Vol.456 (2), p.656-661
Main Authors: Wang, Yuehong, Zhao, Jinjun, Yang, Wei, Bi, Yayan, Chi, Jing, Tian, Juanjuan, Li, Weimin
Format: Article
Language:English
Subjects:
Alcoholic cardiomyopathy
Animals
Apoptosis
Apoptosis - drug effects
Cardiomyocyte
Cardiomyopathy, Alcoholic - enzymology
Cardiomyopathy, Alcoholic - metabolism
Cytochromes c - metabolism
Enzyme Inhibitors - pharmacology
Ethanol - pharmacology
Indoles - pharmacology
Maleimides - pharmacology
Membrane Potential, Mitochondrial - drug effects
Mice
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - enzymology
Myocytes, Cardiac - pathology
Oxidative Stress
p66shc
Phosphorylation
Protein Kinase C beta - antagonists & inhibitors
Protein Kinase C beta - metabolism
Protein kinase C-β
Reactive oxygen species
Reactive Oxygen Species - metabolism
RNA, Small Interfering - genetics
Shc Signaling Adaptor Proteins - genetics
Shc Signaling Adaptor Proteins - metabolism
Signal Transduction
Src Homology 2 Domain-Containing, Transforming Protein 1
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Summary:[Display omitted] •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 (50mM, 100mM, and 200mM). 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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2014.12.012