The objective of the studies described herein are to gain a better understanding of the mechanisms by which chronic alcohol feeding induces derangements in myocardial protein metabolism. Alcoholism remains the most common form of drug abuse in the United States. Alcohol abuse is associated with an increased premature mortality. A leading etilogy of mortality is the development of a cardiomyopathy, diagnosed in approximately 35% of whose individuals who chronically abuse alcohol. The degree of cardiac dysfunction is proportional to the duration and severity of the alcohol consumption. Histological examination of biopsy specimens obtained from humans reveals a thinning of the ventricular wall, myocyte degeneration, loss of striations, and myofilament dissolution, consistent with alterations in structural and myofibrillar proteins. The underlying mechanisms responsible for these alterations remain unknown. It is our hypothesis that chronic alcohol consumption induces specific defects in the regulation of protein synthesis in cardiac muscle that ultimately are responsible for the histologic changes of the alcoholic cardiomyopathy. Preliminary studies have shown a 25% loss of cardiac protein/heart from animals consuming alcohol for 12 weeks. The loss of protein mass resulted, in part, from a diminished (30%) rate of protein synthesis. The block in protein synthesis occurred through an inhibition of translational efficiency, rather than a loss of ribosomes. Furthermore, the diminished translational efficiency is a result of proportional decreases in both peptide-chain initiation and elongation. Currently, there is no information concerning the biochemical loci or mechanism responsible for the inhibition of translational efficiency and hence protein synthesis following chronic ethanol intoxication. The experimental design addresses the following Specific Aims: (1) to determine the mechanism by which chronic alcohol consumption reduces peptide-chain initiation in heart; (2) to determine the mechanism by which chronic alcohol consumption reduces myocardial peptide-chain elongation; 3) to determine the mechanism by which acute alcohol consumption reduces translational efficiency for protein synthesis in heart.; (3) to investigate the expression of specific myocardial proteins following chronic alcohol consumption; and 4) to determine if there is a differential response in protein metabolism to chronic alcohol consumption between male and female rats. Overall, the research design will establish the processes by which myocardial protein synthesis is reduced following long and short term alcohol intoxication.
|Effective start/end date||9/22/00 → 8/31/12|
- National Institutes of Health: $299,260.00