The long-term goal of this project is to elucidate the mechanisms by which moderate consumption o alcohol protects against myocardial ischemic injury. Our working hypothesis is that chronic exposure t( ethanol establishing low levels of oxidative stress in the heart, which elicits an adaptive increase in the myocardial antioxidant defenses and aldehyde metabolism. To test this hypothesis, adult male rats will be fed 6 % ethanol in their drinking water for various periods of time up to 12 weeks. Hearts from these animals, and from control untreated rats, will be excised and perfused ex vivo. The sensitivity of these hearts to ischemia-reperfusion will be determined by subjecting them to 30 and 45 min. of global ischemia, followed by 30 min. of reperfusion. The post-ischemia recovery and myocyte necrosis will be measured. In a parallel series of experiments, the excised hearts will be homogenized and their proteins will be separated by 2-D gel electrophoresis. Changes in myocardial proteins due to chronic ethanol treatment will be identified by image analysis of the gels and by mass spectrometric analysis using matrix-assisted laser desporption ionization (MALDI) and electrospay ionization (ESI). From these experiments a data base wit be developed for categories of proteomic changes and coordinate changes in specific signal and metabolic pathways, and/or transcritional events will be identified. To elucidate the role of aldehyde metabolism, we will examine the extent and the nature of the cardiac metabolism of the prototype lipid peroxidation-derived aldehyde - 4-hydroxy trans-2-nonenal in hearts removed from naive and ethanol-fed animals. To identify the contribution of the changes in aldehyde metabolism, we will examine whether pharmacologica inhibition of the pathways for aldehyde metabolism abrogates the cardioprotective effects of ethanol. The results of this exploratory project will form the basis of future detailed investigations into the mechanism, underlying the cardioprotective effects of ethanol and to identify the regulatory determinants underlying the dose-dependent transition from beneficial to the harmful effects of ethanol.
| Shi, Liang; Wang, Yuan; Tu, Shuyang et al. (2008) The responses of mitochondrial proteome in rat liver to the consumption of moderate ethanol: the possible roles of aldo-keto reductases. J Proteome Res 7:3137-45 |
