A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

Chronic alcohol consumption leads to myocardial injury, ventricle dilation, and cardiac dysfunction, which is defined as alcoholic cardiomyopathy (ACM). To explore the induced myocardial injury and underlying mechanism of ACM, the Liber-DeCarli liquid diet was used to establish an animal model of ACM and histopathology, echocardiography, molecular biology, and metabolomics were employed. Hematoxylin-eosin and Masson’s trichrome staining revealed disordered myocardial structure and local fibrosis in the ACM group. Echocardiography revealed thinning wall and dilation of the left ventricle and decreased cardiac function in the ACM group, with increased serum levels of brain natriuretic peptide (BNP) and expression of myocardial BNP mRNA measured through enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR), respectively. Through metabolomic analysis of myocardium specimens, 297 differentially expressed metabolites were identified which were involved in KEGG pathways related to the biosynthesis of unsaturated fatty acids, vitamin digestion and absorption, oxidative phosphorylation, pentose phosphate, and purine and pyrimidine metabolism. The present study demonstrated chronic alcohol consumption caused disordered cardiomyocyte structure, thinning and dilation of the left ventricle, and decreased cardiac function. Metabolomic analysis of myocardium specimens and KEGG enrichment analysis further demonstrated that several differentially expressed metabolites and pathways were involved in the ACM group, which suggests potential causes of myocardial injury due to chronic alcohol exposure and provides insight for further research elucidating the underlying mechanisms of ACM.

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Effect of chronic alcohol consumption on myocardial apoptosis in the rat model of isoproterenol-induced myocardial injury and investigation on the cardioprotective role of calpain inhibitor 1

Drug and Chemical Toxicology ◽

10.1080/01480545.2021.1985910 ◽

2021 ◽

pp. 1-12

Author(s):

Aysegul Oglakci-Ilhan ◽

Kevser Kusat-Ol ◽

Kubilay Uzuner ◽

Onur Uysal ◽

Ibrahim Sogut ◽

...

Keyword(s):

Alcohol Consumption ◽

Rat Model ◽

Myocardial Injury ◽

Calpain Inhibitor ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

Myocardial Apoptosis

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Cardiac function and metabolism after chronic alcohol consumption: Adaptation, reversibility, and effects of verapamil

American Heart Journal ◽

10.1016/0002-8703(91)90768-d ◽

1991 ◽

Vol 122 (1) ◽

pp. 122-126 ◽

Cited By ~ 11

Author(s):

Wolfgang Auffermann ◽

Shao T. Wu ◽

Joan Wikman-Coffelt ◽

William W. Parmley

Keyword(s):

Alcohol Consumption ◽

Cardiac Function ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption

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Alcohol induced hepatic retinoid depletion is associated with the induction of multiple retinoid catabolizing cytochrome P450 enzymes

PLoS ONE ◽

10.1371/journal.pone.0261675 ◽

2022 ◽

Vol 17 (1) ◽

pp. e0261675

Author(s):

Afroza Ferdouse ◽

Rishi R. Agrawal ◽

Madeleine A. Gao ◽

Hongfeng Jiang ◽

William S. Blaner ◽

...

Keyword(s):

Cytochrome P450 ◽

Retinoic Acid ◽

Liver Disease ◽

Alcohol Consumption ◽

Vitamin A ◽

Alcohol Exposure ◽

Chronic Alcohol ◽

Wild Type ◽

Chronic Alcohol Consumption ◽

Retinyl Esters

Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.

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Chronic Alcohol Consumption and Sex‐Related Differences in Vascular Reactivity and Cardiac Function in Sprague‐Dawley Rats

The FASEB Journal ◽

10.1096/fasebj.20.4.a722-b ◽

2006 ◽

Vol 20 (4) ◽

Author(s):

Christopher Oludare Ladipo ◽

Casmiar Nwaigwe ◽

S A Adigun ◽

Banji Adegunloye ◽

Olusoga Sofola

Keyword(s):

Alcohol Consumption ◽

Cardiac Function ◽

Vascular Reactivity ◽

Chronic Alcohol ◽

Sprague Dawley ◽

Chronic Alcohol Consumption ◽

Sprague Dawley Rats

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Chronic Alcohol Exposure Alters Gene Expression and Neurodegeneration Pathways in the Brain of Adult Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-215508 ◽

2022 ◽

pp. 1-17

Author(s):

Mingjing Liu ◽

Shipeng Guo ◽

Daochao Huang ◽

Dongjie Hu ◽

Yili Wu ◽

...

Keyword(s):

Energy Metabolism ◽

Alcohol Consumption ◽

Alcohol Exposure ◽

Chronic Alcohol ◽

Rna Seq ◽

Chronic Alcohol Consumption ◽

Mitochondrial Energy Metabolism ◽

Brain Transcriptome ◽

Chronic Alcohol Exposure ◽

The Brain

Background: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. Objective: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic “Drinking in the Dark” (DID) mouse model. Methods: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. Results: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. Conclusion: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD.

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Abstract 14641: Deficiency in the E3 Ubiquitin Ligase Parkin Exacerbates Alcoholic Cardiomyopathy: Role of Mitophagy

Circulation ◽

10.1161/circ.130.suppl_2.14641 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Xihui Xu ◽

Jun Ren

Keyword(s):

Alcohol Consumption ◽

Ubiquitin Ligase ◽

Therapeutic Potential ◽

E3 Ubiquitin Ligase ◽

Left Ventricular ◽

Mitochondrial Morphology ◽

Chronic Alcohol ◽

Alcoholic Cardiomyopathy ◽

Chronic Alcohol Consumption

Background: Long-term heavy alcohol consumption has been shown to promote mitochondrial injury, unfavorable geometric and contractile changes in the heart. Parkin, a cytosolic E3 ubiquitin ligase encoded by PARK2 gene, plays an important role in the regulation of selective mitophagy. This study was designed to examine the role of Parkin in alcohol-induced myocardial injury (aka alcoholic cardiomyopathy) and the underlying mechanism with a focus on mitophagy. Methods: Adult male wild-type C57 and PARKIN2 knockout (Parkin-/-) mice were placed on alcohol (4%) or control diet for 4 weeks. Echocardiographic and cardiomyocyte mechanical properties were assessed. Mitochondrial morphology, function and mitophagy were examined using transmission electronic microscopy, Clark-type oxygen electrode, and Western blot, respectively. Results: Our results revealed that chronic alcohol consumption triggered unfavorable geometric and contractile changes [decreased fractional shortening (FS) and ejection fraction (EF), with enlarged left ventricular chamber; decreased peak shortening (PS) and velocity of shortening +dL/dt, increased time-to-90% relengthening TR90], the effects of which were exacerbated by Parkin deficiency. In addition, our data showed that chronic alcohol intake promoted myocardial mitochondrial swelling with cristae disarrangement, induced myocardial mitochondrial depolarization and respiration inhibition, which were exacerbated by Parkin knockout. Furthermore, chronic alcohol consumption promoted mitophagy activation, as evidenced by accumulation of Parkin and LC3BII in mitochondria and mitochondrial ubiquitination level in the heart, the effect of which was nullified by Parkin knockout. Conclusion: These data suggest that chronic alcohol consumption triggered mitophagy by stimulating Parkin translocation to the mitochondria, which may be an adaptive response in the heart. Our findings implicated the therapeutic potential of mitophagy as a target in the management of alcoholic cardiomyopathy.

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