Red wines confer extra benefit when it comes to preventing coronary heart disease.

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Posted by Corder et al (160.129.27.22) on January 02, 2002 at 20:46:58:

Nature 414, 863 - 864 (Dec. 18/27 2001) © Macmillan Publishers Ltd.

Health: Endothelin-1 synthesis reduced by red wine

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 aggregation2-4, 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).

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 0.4 l ml-1). Red-grape juice also inhibits ET-1 synthesis, but is markedly less potent than red wine (IC50 = 35 l ml-1). The white and rosé wines had no effect on ET-1 synthesis (>5% inhibition at 100 l 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 M) 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.

Supplementary information is available on Nature's World-Wide Web site (http://www.nature.com) or as paper copy from the London editorial office of Nature.

ROGER CORDER, JULIE A. DOUTHWAITE, DELPHINE M. LEES, NOORAFZA Q. KHAN, ANA CAROLINA VISEU DOS SANTOS, ELIZABETH G. WOOD & MARTIN J. CARRIER
William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

References:
1. St Leger, A. S., Cochrane, A. L. & Moore, F. Lancet i, 1017-1020 (1979).

2. Renaud, S. & De Lorgeril, M. Lancet i, 1523-1526 (1992).

3. Doll, R., Peto, R., Hall, E., Wheatley, K. & Gray, R. Br. Med. J. 309, 911-918 (1994).

4. Law, M. & Wald, N. Br. Med. J. 318, 1471-1476 (1999).

5. Goldberg, I. J., Mosca, L., Piano, M.R. & Fisher, E. A. Circulation 103, 472-475 (2001).

6. Corder, R. in Handbook of Experimental Pharmacology: Endothelin and its Inhibitors (ed. Warner, T. D.) 152, 35-67 (Springer, Berlin, 2001).

7. Yanagisawa, M. et al. Nature 332, 411-415 (1988).

8. Caligiuri, G., Levy, B., Pernow, J., Thorén, P. & Hansson, G. K. Proc. Natl Acad. Sci. USA 96, 6920-6924 (1999).

9. Kinlay, S. et al. Circulation 104, 1114-1118 (2001).

10. Frankel, E. N., Kanner, J., German, J. B., Parks, E. & Kinsella, J. E. Lancet 341, 454-457 (1993)

11. Diebolt, M., Bucher, B. & Andriantsitohaina, R. Hypertension 38, 159-165 (2001).

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: Nature 414, 863 - 864 (Dec. 18/27 2001) © Macmillan Publishers Ltd. : : : Health: Endothelin-1 synthesis reduced by red wine : 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 aggregation2-4, 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). : 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 0.4 l ml-1). Red-grape juice also inhibits ET-1 synthesis, but is markedly less potent than red wine (IC50 = 35 l ml-1). The white and rosé wines had no effect on ET-1 synthesis (>5% inhibition at 100 l 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 M) 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. : Supplementary information is available on Nature's World-Wide Web site (http://www.nature.com) or as paper copy from the London editorial office of Nature. : : ROGER CORDER, JULIE A. DOUTHWAITE, DELPHINE M. LEES, NOORAFZA Q. KHAN, ANA CAROLINA VISEU DOS SANTOS, ELIZABETH G. WOOD & MARTIN J. CARRIER : William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK : : References: : 1. St Leger, A. S., Cochrane, A. L. & Moore, F. Lancet i, 1017-1020 (1979). : 2. Renaud, S. & De Lorgeril, M. Lancet i, 1523-1526 (1992). : 3. Doll, R., Peto, R., Hall, E., Wheatley, K. & Gray, R. Br. Med. J. 309, 911-918 (1994). : 4. Law, M. & Wald, N. Br. Med. J. 318, 1471-1476 (1999). : 5. Goldberg, I. J., Mosca, L., Piano, M.R. & Fisher, E. A. Circulation 103, 472-475 (2001). : 6. Corder, R. in Handbook of Experimental Pharmacology: Endothelin and its Inhibitors (ed. Warner, T. D.) 152, 35-67 (Springer, Berlin, 2001). : 7. Yanagisawa, M. et al. Nature 332, 411-415 (1988). : 8. Caligiuri, G., Levy, B., Pernow, J., Thorén, P. & Hansson, G. K. Proc. Natl Acad. Sci. USA 96, 6920-6924 (1999). : 9. Kinlay, S. et al. Circulation 104, 1114-1118 (2001). : 10. Frankel, E. N., Kanner, J., German, J. B., Parks, E. & Kinsella, J. E. Lancet 341, 454-457 (1993) : 11. Diebolt, M., Bucher, B. & Andriantsitohaina, R. Hypertension 38, 159-165 (2001).

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