ENDOTHELIAL CELL FIBRINOLYSIS INDUCED BY WINE PHENOLICS

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Dr. Aikens will become an Assistant Professor of Medicine on July 1, 1999, in the Division of Cardiovascular Diseases (DCD) at UAB. Dr. Aikens s subspecialty training is in the area of Preventative Cardiology with a research interest in vascular biology. He has won several distinguished departmental awards for his research cardioprotective effects of alcohol on endothelial cell(EC)-mediated fibrinolysis and has presented his research at several national meetings. His proposal will define the relationship between red wine phenolic compounds and sustained increases of EC mediated fibrinolysis, which may contribute, in part, to cardioprotection. Since the reduced risk for CAD has been attributed to moderate red wine consumption, which may be due to the combined effects of ethanol and the antioxidant potential or other effects of phenolic compounds in wine. It is conceivable that selected wine phenolic compounds, resveratrol, quercetin and catechin may have additional properties which may affect EC function in the long-term, in particular fibrinolysis, independent of their direct short-term antioxidant properties. These preliminary studies were carried out to determine whether select wine phenolics may, in fact, induce the expression of either t-PA and/or u-PA, resulting in a significant sustained increased expression of EC fibrinolytic activity. Wine phenolic-induced increased surface-localized EC fibrinolytic activity (preliminary studies) may be expected to decrease thrombotic risk. Selected wine phenolics will exert a sustained long-term (24 h) increase in EC fibrinolysis by increasing the catalytic efficiency of surface-localized plasmin generation (ligand binding) (Aim 1) resulting from the transcriptional upregulation of t-PA and u-PA gene expression(transcription run-on, transfection)(Aim 2) through factor(s) that bind to specific cis-acting regulatory region(s) in the PAs promoters(promoter deletion analysis) (Aim 3). UAB, Department of Medicine and DCD will provide the research space, facilities, resources (secretarial support and office space) and appropriate time commitment (75 percent) to allow the candidate to conduct and accomplish the research goals set forth in this application. He will have no administrative or teaching duties during the period of this application. If his faculty sponsor were to leave the institution, a new sponsor will be appointed and his continued development toward becoming an independent physician, scientist will be supported and encouraged.