Abstract
ObjectivesBinge 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).MethodsADH 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.ResultsEthanol 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 O2 •−. 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-α, Fas receptor, Fas L and cytosolic AIF.ConclusionsTaken 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.
Highlights
Alcohol exposure often results in the development of alcoholic cardiomyopathy characterized by cardiomegaly, disruption of myofibrillary architecture and myocardial dysfunction [1,2]
Given that apoptosis and mitochondrial damage are commonly present in response to ethanol challenge and are thought to play an essential role in alcoholism-elicited organ damage and complications [9,11], our current study was designed to address the role of mitochondrial function and apoptosis in ethanol-induced myocardial dysfunction
Cardiac acetaldehyde levels were significantly increased following ethanol challenge, the effect of which was exacerbated by the alcohol dehydrogenase (ADH) transgene (Table 1)
Summary
Alcohol (ethanol) exposure often results in the development of alcoholic cardiomyopathy characterized by cardiomegaly (dilated cardiomyopathy), disruption of myofibrillary architecture and myocardial dysfunction [1,2]. Facilitated clearance of acetaldehyde via mitochondrial aldehyde dehydrogenase (ALDH-2) was shown to be beneficial in alleviating acute and chronic ethanol exposureinduced contractile dysfunction and/or myocardial hypertrophy [9,10], further supporting the detrimental role of acetaldehyde in alcohol-induced myocardial damage. The precise mechanism of action behind the acetaldehyde-induced unfavorable myocardial functional and morphological changes following either acute or chronic ethanol exposure remains elusive. The death receptor pathway is usually triggered by the linkage of specific ligands to membrane receptors including tumor necrosis factor a (TNF-a) and Fas receptor [14] To this end, expression of TNF-a, Fas, Fas ligand (FasL), Caspase and pro-caspase-8 was examined in wild-type FVB and ADH hearts following acute ethanol challenge. TUNEL assay and levels of the pro-apoptotic proteins Bax and Caspase-3 as well as the anti-apoptotic protein Bcl-2 were used as for overall assessment of apoptosis
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