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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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Cardiac hypertrophy and apoptosis following ethanol exposure: Expression of the hypertrophic marker ANP and apoptosis-related proteins in myocardium from FVB and ADH mice with or without acute ethanol exposure.A: ANP; B: Bax; C: Bcl-2; and D: Caspase-3. Insets: Representative gel blots depicting expression of ANP, Bax, Bcl-2, Caspase-3 and α-Tubulin (loading control). Mean ± SEM, n = 5–10 samples per group, all samples were in duplicates with the average being used, * p<0.05 vs. FVB, # p<0.05 vs. FVB-EtOH group.
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pone-0008757-g006: Cardiac hypertrophy and apoptosis following ethanol exposure: Expression of the hypertrophic marker ANP and apoptosis-related proteins in myocardium from FVB and ADH mice with or without acute ethanol exposure.A: ANP; B: Bax; C: Bcl-2; and D: Caspase-3. Insets: Representative gel blots depicting expression of ANP, Bax, Bcl-2, Caspase-3 and α-Tubulin (loading control). Mean ± SEM, n = 5–10 samples per group, all samples were in duplicates with the average being used, * p<0.05 vs. FVB, # p<0.05 vs. FVB-EtOH group.

Mentions: Our data revealed that neither acute ethanol challenge nor ADH transgene affected the hypertrophic marker ANP expression. In line with the TUNEL assay observation, our further results indicated that ethanol treatment significantly increased expression of the pro-apoptotic proteins Bax and Caspase-3 while decreasing the level of the anti-apoptotic protein Bcl-2. Although ADH failed to alter the ethanol-induced response of Caspase-3, it significantly augmented ethanol-elicited responses in Bax and Bcl-2. ADH transgene itself did not elicit any effect on the expression of Bax, Bcl-2 and Caspase-3 in the absence of ethanol treatment (Fig. 6). We went on to examine the involvement of the death receptor and mitochondrial death pathways in ADH and ethanol-associated apoptotic effects. Neither ethanol nor ADH transgene affected the levels of the main death receptor apoptotic proteins TNFα, Fas receptor and Fas ligand (FasL) and Caspase-8 (Fig. 7). Examination of the mitochondrial death pathway depicted that acute ethanol treatment significantly promoted cytosolic accumulation of cytochrome C and pro-caspase-9, the effect of which was augmented by ADH. Neither ethanol nor ADH altered the levels of total pro-caspase-9, cytosolic AIF and the death receptor mediator cytosolic pro-caspase-8 (Fig. 8).


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

Guo R, Ren J - PLoS ONE (2010)

Cardiac hypertrophy and apoptosis following ethanol exposure: Expression of the hypertrophic marker ANP and apoptosis-related proteins in myocardium from FVB and ADH mice with or without acute ethanol exposure.A: ANP; B: Bax; C: Bcl-2; and D: Caspase-3. Insets: Representative gel blots depicting expression of ANP, Bax, Bcl-2, Caspase-3 and α-Tubulin (loading control). Mean ± SEM, n = 5–10 samples per group, all samples were in duplicates with the average being used, * 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-g006: Cardiac hypertrophy and apoptosis following ethanol exposure: Expression of the hypertrophic marker ANP and apoptosis-related proteins in myocardium from FVB and ADH mice with or without acute ethanol exposure.A: ANP; B: Bax; C: Bcl-2; and D: Caspase-3. Insets: Representative gel blots depicting expression of ANP, Bax, Bcl-2, Caspase-3 and α-Tubulin (loading control). Mean ± SEM, n = 5–10 samples per group, all samples were in duplicates with the average being used, * p<0.05 vs. FVB, # p<0.05 vs. FVB-EtOH group.
Mentions: Our data revealed that neither acute ethanol challenge nor ADH transgene affected the hypertrophic marker ANP expression. In line with the TUNEL assay observation, our further results indicated that ethanol treatment significantly increased expression of the pro-apoptotic proteins Bax and Caspase-3 while decreasing the level of the anti-apoptotic protein Bcl-2. Although ADH failed to alter the ethanol-induced response of Caspase-3, it significantly augmented ethanol-elicited responses in Bax and Bcl-2. ADH transgene itself did not elicit any effect on the expression of Bax, Bcl-2 and Caspase-3 in the absence of ethanol treatment (Fig. 6). We went on to examine the involvement of the death receptor and mitochondrial death pathways in ADH and ethanol-associated apoptotic effects. Neither ethanol nor ADH transgene affected the levels of the main death receptor apoptotic proteins TNFα, Fas receptor and Fas ligand (FasL) and Caspase-8 (Fig. 7). Examination of the mitochondrial death pathway depicted that acute ethanol treatment significantly promoted cytosolic accumulation of cytochrome C and pro-caspase-9, the effect of which was augmented by ADH. Neither ethanol nor ADH altered the levels of total pro-caspase-9, cytosolic AIF and the death receptor mediator cytosolic pro-caspase-8 (Fig. 8).

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