Brief Communications
Nature 414, 863-864 (20 December 2001) | doi:10.1038/414863a
Health: Endothelin-1 synthesis reduced by red wine
Roger Corder1, Julie A. Douthwaite1, Delphine M. Lees1, Noorafza Q. Khan1, Ana Carolina Viseu dos Santos1, Elizabeth G. Wood1 and Martin J. Carrier1
Red wines confer extra benefit when it comes to preventing coronary heart disease.
Statistical evidence of reduced coronary heart disease in areas of high wine consumption has led to the widespread belief that wine affords a protective effect1, 2. Although moderate drinking of any alcohol helps to reduce the incidence of coronary heart disease3, 4, there is no clear evidence that red wine confers an additional benefit5. Here we show that red wines strongly inhibit the synthesis of endothelin-1, a vasoactive peptide that is crucial in the development of coronary atherosclerosis6. Our findings indicate that components specific to red wine may help to prevent coronary heart disease.
The concept of the 'French paradox' has arisen from reports that deaths from coronary heart disease are much lower in France than in the United Kingdom, despite a comparable dietary intake of saturated fats by these populations1, 2 — this has been attributed to the higher consumption of alcohol in France, particularly of wine1, 2. Mechanisms implicated in this phenomenon include increases in high-density lipoproteins (HDLs) and fibrinolytic activity, and decreased platelet aggregation2, 3, 4, but these changes are modest and can also be caused by ethanol consumption per se3, 4. Indeed, the very existence of the French paradox has been questioned as it may simply reflect a time lag in dietary cholesterol intake4. Identification of a specific property of red wine that accounts for reductions in coronary heart disease could resolve this controversy, as well as providing insight into the health benefits of a Mediterranean diet.
Endothelin-1 (ET-1) was originally described as a highly potent vasoconstrictor peptide7, and its overproduction is seen as a key factor in the development of vascular disease and atherosclerosis6. Experimental models of atherosclerosis indicate that endothelin antagonists prevent manifestation of the early stages of the disease, such as endothelial dysfunction or fatty-streak formation6, and reduce myocardial infarction in established disease8. The coronary blood supply of patients with coronary heart disease is also severely perturbed by local ET-1 production9. We investigated whether red wine could inhibit the synthesis of ET-1, as this might explain its cardioprotective properties.
We found that polyphenols from red wine made from Cabernet Sauvignon grapes decreased ET-1 synthesis in cultured bovine aortic endothelial cells (BAECs) by suppressing transcription of the ET-1 gene (Fig. 1a). To test whether this property is peculiar to red wine, we prepared ethanol-free extracts from 23 red wines, four white wines, one rosé wine and one red-grape juice (see supplementary information for details). These extracts were tested on BAECs to determine the concentration of each wine that causes a 50% reduction in basal ET-1 synthesis (IC50) (Fig. 1b).
Figure 1: Red wine inhibits endothelin-1 (ET-1) synthesis by bovine aortic endothelial cells and alters the distribution of phosphotyrosine immunofluorescence.
Figure 1 : Red wine inhibits endothelin-1 (ET-1) synthesis by bovine aortic endothelial cells and alters the distribution of phosphotyrosine immunofluorescence. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com
a, Red wine extract suppresses ET-1 release (red bars) and transcription of the prepro-ET-1 gene (ET-1 reporter gene activity; blue bars). b, ET-1 release over 6 h during incubation with extracts of red-grape juice (triangles) and a representative red wine (circles) (plotted as equivalent dilutions to unextracted samples). c, Correlation of total polyphenol content of red wine (measured with Folin and Ciocalteu's reagent and expressed as catechin equivalents in mumol ml -1) with the concentration of red-wine extract causing a 50% reduction in basal ET-1 synthesis (IC50, expressed as mul-equivalents of unextracted wine per ml culture medium) (see supplementary information for details). d, e, After 1 h treatment of bovine aortic endothelial cells with either medium or red-wine extract (50 mug ml-1), phosphotyrosine (PY)-containing proteins in permeabilized cells were detected as brightly staining regions by using anti-PY monoclonal antibody 4G10 and FITC-labelled goat anti-mouse IgG. d, Control cells incubated with medium; e, cells after treatment with red-wine extract. Original magnification, times 100.
High resolution image and legend (42K)
For the red wines, the degree of inhibition of ET-1 synthesis was correlated with the total polyphenol content (Fig. 1c; r2 = 0.46, mean IC50 = 5.0 plusminus 0.4 mul ml-1). Red-grape juice also inhibits ET-1 synthesis, but is markedly less potent than red wine (IC50 = 35 mul ml-1). The white and rosé wines had no effect on ET-1 synthesis (>5% inhibition at 100 mul ml-1). As the rosé wine was from Cabernet Sauvignon grapes, this indicates that the active principle in red wine must derive from red-grape skins or other grape components during the vinification process.
Although polyphenols in red wines are known to have antioxidant properties10, it is unlikely that this accounts for the effect on ET-1 synthesis. For instance, quercetin (10 muM) totally inhibits the oxidation of low-density lipoproteins (LDLs)10; however, at this concentration neither red-wine polyphenols (quercetin, resveratrol, d,l-catechin, d,l-epicatechin) nor anthocyanins (delphinidin, pelargonidin, cyanidin, peonidin, petunidin, malvidin) affect ET-1 production.
Inhibitors of the cellular tyrosine-kinase family of phosphorylating enzymes that share structural similarity to red-wine polyphenols also suppress ET-1 synthesis6. We therefore investigated whether this action of red wine might be explained by an inhibitory effect on this same family of enzymes by using immunocytochemistry to visualize tyrosine phosphorylation in endothelial cells. Compared with control cells, red-wine extract causes a marked change in cell morphology and a redistribution of phosphotyrosine staining (Fig. 1d, e). These effects on tyrosine phosphorylation are presumably due to modified tyrosine-kinase signalling in endothelial cells.
Red-wine extract is also known to elicit endothelium-dependent vasodilation and lower blood pressure11, which may provide further protection against coronary heart disease. Our findings indicate that remarkably small amounts of red-wine extract can suppress ET-1 synthesis: assuming adequate absorption of the active component, they support assertions that a moderate intake of red wine can prevent coronary heart disease. Characterization of the vascular mechanisms underlying red wine's beneficial effects should help in the design of strategies to prevent atherosclerosis.
Competing interests statement:
The authors declared no competing interests.
Supplementary information accompanies this paper.
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1. William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Correspondence to: Roger Corder1 e-mail: Email: r.corder@qmul.ac.uk
