Mechanism by which alcohol and wine polyphenols affect coronary heart disease risk.
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.
Booyse
Francois M
FM
University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA.
Pan
Wensheng
W
Grenett
Hernan E
HE
Parks
Dale A
DA
Darley-Usmar
Victor M
VM
Bradley
Kelley M
KM
Tabengwa
Edlue M
EM
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
D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D000431:Ethanol; D010959:Tissue Plasminogen Activator