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Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.

Guo R, Ren J - PLoS ONE (2010)

Bottom Line: Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown.Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene.In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-).

View Article: PubMed Central - PubMed

Affiliation: Center for Cardiovascular Research and Alternative Medicine, College of Health Sciences, University of Wyoming, Laramie, Wyoming, United States of America.

ABSTRACT

Objectives: Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH).

Methods: ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways) were examined.

Results: Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-). Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-alpha, Fas receptor, Fas L and cytosolic AIF.

Conclusions: Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.

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Mitochondrial function following ethanol exposure: Cardiomyocyte mitochondrial membrane potential (MMP) in FVB and ADH mice with or without acute ethanol exposure.JC-1 fluorochrome was shown as the ratio of red to green fluorescence. CCCP was used a positive control. Mean ± SEM, n = 9–14 cells per group, * p<0.05 vs. FVB, # p<0.05 vs. FVB-EtOH group.
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pone-0008757-g004: Mitochondrial function following ethanol exposure: Cardiomyocyte mitochondrial membrane potential (MMP) in FVB and ADH mice with or without acute ethanol exposure.JC-1 fluorochrome was shown as the ratio of red to green fluorescence. CCCP was used a positive control. Mean ± SEM, n = 9–14 cells per group, * p<0.05 vs. FVB, # p<0.05 vs. FVB-EtOH group.

Mentions: To evaluate mitochondrial integrity and function, mitochondrial O2•− production and membrane potential were detected using the MitoSOX Red and JC-1 fluorescent probes, respectively. Our data revealed that acute ethanol exposure significantly promoted mitochondrial O2•− production and decreased mitochondrial membrane potential in cardiomyocytes, the effects of which were accentuated by ADH. The ADH transgene itself did not elicit any significant effect on mitochondrial O2•− production or mitochondrial membrane potential (Fig. 3 and Fig. 4). Moreover, the ADH enzymatic metabolite of ethanol, acetaldehyde (100 µM), significantly promoted mitochondrial O2•− production (Fig. 3F).


Alcohol dehydrogenase accentuates ethanol-induced myocardial dysfunction and mitochondrial damage in mice: role of mitochondrial death pathway.

Guo R, Ren J - PLoS ONE (2010)

Mitochondrial function following ethanol exposure: Cardiomyocyte mitochondrial membrane potential (MMP) in FVB and ADH mice with or without acute ethanol exposure.JC-1 fluorochrome was shown as the ratio of red to green fluorescence. CCCP was used a positive control. Mean ± SEM, n = 9–14 cells per group, * p<0.05 vs. FVB, # p<0.05 vs. FVB-EtOH group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2807457&req=5

pone-0008757-g004: Mitochondrial function following ethanol exposure: Cardiomyocyte mitochondrial membrane potential (MMP) in FVB and ADH mice with or without acute ethanol exposure.JC-1 fluorochrome was shown as the ratio of red to green fluorescence. CCCP was used a positive control. Mean ± SEM, n = 9–14 cells per group, * p<0.05 vs. FVB, # p<0.05 vs. FVB-EtOH group.
Mentions: To evaluate mitochondrial integrity and function, mitochondrial O2•− production and membrane potential were detected using the MitoSOX Red and JC-1 fluorescent probes, respectively. Our data revealed that acute ethanol exposure significantly promoted mitochondrial O2•− production and decreased mitochondrial membrane potential in cardiomyocytes, the effects of which were accentuated by ADH. The ADH transgene itself did not elicit any significant effect on mitochondrial O2•− production or mitochondrial membrane potential (Fig. 3 and Fig. 4). Moreover, the ADH enzymatic metabolite of ethanol, acetaldehyde (100 µM), significantly promoted mitochondrial O2•− production (Fig. 3F).

Bottom Line: Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown.Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene.In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-).

View Article: PubMed Central - PubMed

Affiliation: Center for Cardiovascular Research and Alternative Medicine, College of Health Sciences, University of Wyoming, Laramie, Wyoming, United States of America.

ABSTRACT

Objectives: Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown. This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility, mitochondrial function and apoptosis using a murine model of cardiac-specific overexpression of alcohol dehydrogenase (ADH).

Methods: ADH and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Myocardial contractility, mitochondrial damage and apoptosis (death receptor and mitochondrial pathways) were examined.

Results: Ethanol led to reduced cardiac contractility, enlarged cardiomyocyte, mitochondrial damage and apoptosis, the effects of which were exaggerated by ADH transgene. In particular, ADH exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O(2) (*-). Myocardium from ethanol-treated mice displayed enhanced Bax, Caspase-3 and decreased Bcl-2 expression, the effect of which with the exception of Caspase-3 was augmented by ADH. ADH accentuated ethanol-induced increase in the mitochondrial death domain components pro-caspase-9 and cytochrome C in the cytoplasm. Neither ethanol nor ADH affected the expression of ANP, total pro-caspase-9, cytosolic and total pro-caspase-8, TNF-alpha, Fas receptor, Fas L and cytosolic AIF.

Conclusions: Taken together, these data suggest that enhanced acetaldehyde production through ADH overexpression following acute ethanol exposure exacerbated ethanol-induced myocardial contractile dysfunction, cardiomyocyte enlargement, mitochondrial damage and apoptosis, indicating a pivotal role of ADH in ethanol-induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis.

Show MeSH
Related in: MedlinePlus