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Mechanism by which alcohol and wine polyphenols affect coronary heart disease risk
Francois M Booyse1, Wensheng Pan, Hernan E Grenett
1University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA.
Insights
Moderate alcohol and polyphenol intake enhances fibrinolysis, reducing coronary heart disease risks. This study details how these compounds increase blood clot lysis by modulating endothelial cell function.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Pharmacology
Background:
- Moderate alcohol consumption is linked to reduced coronary heart disease (CHD), potentially via enhanced fibrinolysis.
- Endothelial cell (EC)-mediated fibrinolysis is crucial for mitigating acute atherothrombotic events like myocardial infarction (MI).
- Alcohol and polyphenols influence EC fibrinolytic protein expression, impacting overall fibrinolytic activity.
Purpose of the Study:
- To elucidate the molecular mechanisms by which alcohol and polyphenols increase EC tissue plasminogen activator (t-PA) expression.
- To investigate the impact of alcohol and polyphenol treatment on in vitro and in vivo fibrinolysis.
- To assess the therapeutic potential of alcohol, catechins, and quercetin in normalizing impaired clot lysis in an atherosclerosis model.
Main Methods:
- Analysis of EC fibrinolytic protein expression (t-PA, u-PA, PAI-1, u-PAR, Annexin-II) at cellular, molecular, and gene levels.
- Investigation of p38 MAPK signaling pathway activation.
- In vivo studies using real-time fluorescence imaging of Cy5.5-labeled fibrin clot lysis in C56Bl/6 and ApoE knock-out mice.
Main Results:
- Alcohol and polyphenols (catechins, quercetin) significantly increase EC t-PA gene transcription and subsequent fibrinolytic activity.
- In vivo studies demonstrated significantly increased clot lysis rates in mice treated with alcohol, catechins, or quercetin.
- Treatment with alcohol, catechins, or quercetin normalized impaired in vivo clot lysis in ApoE knock-out mice, suggesting atheroprotective effects.
Conclusions:
- Alcohol and specific polyphenols enhance endothelial fibrinolytic capacity through p38 MAPK signaling, leading to increased clot lysis.
- These findings provide a molecular basis for the cardioprotective effects of moderate alcohol and polyphenol consumption.
- Alcohol, catechins, and quercetin show potential for therapeutic intervention in conditions with impaired fibrinolysis, such as atherosclerosis.
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.
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