Project Details

Description

DESCRIPTION (provided by applicant): Chronic alcoholism is a major cause of cardiomyopathy in humans and leads to a variety of changes that interfere with contractile function in the hearts of ethanol-fed animal models. Features of alcoholic cardiomyopathy include decreased cardiac output, impaired myocardial contractility and atrial dysrhythmias. There are also direct cardiodepressant effects of alcohol during acute administration. Some of the features of alcoholic heart disease may reflect adaptive changes induced by these acute ethanol actions. Our studies during the previous granting period have identified a number of targets of acute ethanol action within the excitation-contraction (E-C) coupling cascade, including sarcolemmal Na+ and Ca2+ channels, which lead to depression of the cytosolicCa2+ ([Ca2+]i) transients that drive contraction. We have also identified specific changes in E C coupling in the hearts of ethanol-fed rats, which suggest a selective lesion in the L-type Ca2+ channel and its regulation by cAMP-dependent protein kinase. In the work proposed here, we will further investigate the elements of E C coupling that are affected by acute ethanol, with a view to elucidating which of these is likely to contribute to the deficient [Ca2+]i transients. However, the principal aims of the proposed studies will be to characterize the changes in E C coupling following chronic ethanol consumption, and to determine the mechanism of these changes and how they lead to deficiencies in cardiac function. Specifically, we will investigate the following linked hypotheses: Alterations in the channel subunit isoform composition and/or expression leads to a channel that is defective, either in (1) basal channel properties, (2) coupling to intracellular Ca2+ release pathways, (3) regulation by the normal cAMP-dependent signaling pathway, and/or (4) localization within the cardiomyocyte. These experiments will utilize a combination of [Ca2+]i imaging, electrophysiology and molecular biology approaches. The proposed work will yield new insights into the changes in E C coupling that underlie cardiac dysfunction induced by chronic ethanol consumption. These findings may also have broader implications in elucidating the causal factors associated with the development of other aberrant adaptive processes in the heart, which eventually lead to cardiac failure
StatusFinished
Effective start/end date5/1/044/30/11

Funding

  • National Institutes of Health: $326,483.00
  • National Institutes of Health: $336,000.00
  • National Institutes of Health: $336,234.00
  • National Institutes of Health: $344,325.00
  • National Institutes of Health: $156,000.00
  • National Institutes of Health: $331,745.00

ASJC

  • Medicine(all)

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