title: Mechanism by which alcohol and wine polyphenols affect coronary heart disease risk.
abstract: The reduction in coronary heart disease (CHD) from moderate alcohol intake may be mediated, in part, by increased fibrinolysis; endothelial cell (EC)-mediated fibrinolysis should decrease acute atherothrombotic consequences (eg, plaque rupture) of myocardial infarction (MI). We have shown that alcohol and individual polyphenols modulate EC fibrinolytic protein (t-PA, u-PA, PAI-1, u-PAR and Annexin-II) expression at the cellular, molecular, and gene levels to sustain increased fibrinolytic activity. Herein we describe the sequence of molecular events by which EC t-PA expression is increased through common activation of p38 MAPK signaling. Up-regulation of t-PA gene transcription, through specific alcohol and polyphenol transcription factor binding sites in the t-PA promoter, results in increased in vitro fibrinolysis and in vivo clot lytic activity (using real-time fluorescence [Fl] imaging of Cy5.5-labeled fibrin clot lysis in a mouse model). Fl-labeled fibrin clots injected into untreated C56Bl/6 wild-type control mice are lysed in approximately 2 hours and clot lytic rates significantly increased in mice treated with either alcohol, catechins, or quercetin (4-6 weeks). Fl-labeled clot lysis in ApoE knock-out mice (atherosclerosis model) showed impaired in vivo clot lysis that was "normalized" to wild-type control levels by treatment with alcohol, catechin, or quercetin for 6 to 8 weeks.
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA.
authors.forename: Francois M
authors.initials: FM
authors.lastname: Booyse
authors.forename: Wensheng
authors.initials: W
authors.lastname: Pan
authors.forename: Hernan E
authors.initials: HE
authors.lastname: Grenett
authors.forename: Dale A
authors.initials: DA
authors.lastname: Parks
authors.forename: Victor M
authors.initials: VM
authors.lastname: Darley-Usmar
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Bradley
authors.forename: Edlue M
authors.initials: EM
authors.lastname: Tabengwa
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D003327:Coronary Disease / Q000453:epidemiology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000187:drug effects; D014920:Wine
chemical_list: D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D000431:Ethanol; D010959:Tissue Plasminogen Activator