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Resveratrol and non-ethanolic components of wine in experimental cardiology
100
Nutr Metab Cardlovasc Dis (2003) 13. 100-103
VIEWPOINT
Resveratrol and non-ethanolic components of wine in experimental cardiology M. de Lorgeril, P. Salen, A. Guiraud, E Boucher, and J. de Leiris Laboratolre du Stress Cardlovasculalre et Pathologies Assocl6es, Umverslt6 Joseph Fourier, Grenoble, France
Abstract The mechanisms through which the consumption of alcoholic beverages, in particular wine, protects against cardiac and vascular diseases remain largely unexplored. New methods are needed to investigate that crucial medical and scientific question. Several groups are now beginning to use animal models of myocardial ischemia and reperfusion to explore whether certam nutrients, including ethanol and non-ethanolic components of wine, may have a specific protective effect on the myocardium, independently from the classical risk factors involved in vascular atherosclerosis and thrombosis. Concepts used tn experimental cardiology, such as preconditioning and stunning, are now entering the field of nutritton, and this will undoubtedly lead to constderable improvements in the prevention and treatment of cardtovascular diseases. Nutr Metab Cardiovasc Dis (2003) 13:100-103 ~2003, Medlkal Press
A number of epidemaological studies have reported decreased cardiovascular mortality and morbidity among moderate alcohol drinkers as compared with abstainers (1-8). Considerable controversy has arisen regarding the mechanisms that may be responsible for alcohol-induced cardiac protection, and several different mechanisms have been suggested. These include an effect on blood liplds and platelets resulting in a decreased rate of atherosclerotic and thrombotic coronary artery obstruction (9-11). However, other
Key-words Resveratrol, ethanol, non-ethanohc components of wine, experimental cardiology Correspondence to M de Lorgerll, Laboratolre du Stress Cardaovasculalreet Pathologies Assocl6es, UFR de M6declne et Pharmacle, Domalne de la Merci, 38706 La Tronche (Grenoble), France E-mad mlchel.delorgenl@ulf-grenoble fr
mechanisms are probably involved. For instance, recent studies have shown that moderate drinking may improve early outcomes after acute myocardial infarction and may prevent sudden cardiac death (12-15), which suggests a direct protective effect on the myocardium. Thus, regular ethanol consumption may mimic the classical ischemic preconditioning (IPC) and protect against ischemia and repeffusion injury. What is IPC? IPC is a phenomenon in which single or multiple brief periods of ischemia have been shown to protect the heart against a more prolonged ischemic insult, thus resulting in a marked reduction in myocardial infarct size, the severity of stunning, or the incidence of ventricular arrhythmias (16). All these consequences are potentially important in the clinical settings. Many groups have tried and are still trying to understand the mechanisms of IPC in order to design new pharmacological approaches (and to market new drugs) for the treatment and prevention of coronary heart disease (CHD). Despite a lot of brilliant and optimistic publications in that field (in particular those related to the protective effect of antioxidant, anti-leukocyte and anti-inflammatory compounds during reperfusion) over the past twenty years, one may reasonably say that this experimental approach has been rather disappointing. No major drug based on the concept of IPC has emerged for clinical use. One major exception, however, is the discovery that ethanol drinking may mimic IPC. In fact, several groups have reported that ethanol protects the heart against ischemia and reperfusion injury (17-21). On the other hand, beside the cardioprotective effect of ethanol itself, non-ethanolic components of wine may be involved in the protection resulting from their consumption, at least when taken in moderate amounts. As regards these components, in contrast with alcoholic beverages in general, there are only a few clinical or epidemiological data to support that assumption. For instance, studies sup-
Resveratrol in experimental cardiology
port a protective effect of fiavonoids, especially when taken with tea or wine (22). However, no human trial has been designed so far to test these compounds, which are probably responsible for the antioxidant activity of wine. The beneficial effect of wine drinking has been attributed, at least partly, to the antioxidants present in its polyphenol fraction, which include catechin, proanthocyanidins and resveratrol. It is noteworthy that grape seed proanthocyanidins were actually shown to have cardiac protective effects against reperfusion-induced injury in a rat model of myocardial ischemia, via their ability to reduce or remove, directly or indirectly, free radicals in the myocardium being reperfused after ischemia (23). Further studies are however required to confirm these interesting data. On the other hand, resveratrol, a naturally occurring phenolic compound found in great amounts in grape skins and in wines, has been found to protect the heart from ischemiareperfusion injury (24). Preconditioning of the heart with resveratrol resulted in both reduced infarct size and improved postischemic ventricular functional recovery. This is an important point because IPC in the rat model has never been associated with a beneficial effect on postischemic left ventricular function. It was hypothesized that resveratrol could pharmacologically precondition the heart in a nitric oxide (NO)-dependent manner. As a matter of fact, resveratrol was unable to precondition inducible NO synthase (iNOS) knockout mouse heart, whereas it could successfully precondition wild-type mouse hearts, which indicates an essential role of iNOS in cardiac resveratrol preconditioning (25). In fact, using cultured human vein endothelial cell, resveratrol was also shown to up-regulate endothelial NOS mRNA expression in a time- and concentration-dependent manner (26). Resveratrol also enhanced the production of bioactive NO and increased the activity of the endothelial NOS gene promoter (26). All these data suggest, but do not prove, that resveratrol may protect the heart by acting on the endothelial NOS. In addition, it was shown that a reasonable consumption of certain resveratrol-rich wines results in a significant accumulation of that lipophilic substance in tissues such as the heart and the kidneys (27). Thus, the preconditioning effect of resveratrol may be dependent of its presence in situ. One point that remains to explain is what is the molecular target of resveratrol in the myocardium. In the article published in the current issue of NMCD (28), Savouret et al propose that resveratrol is a ligand (with antagonistic abilities) of the Aryl Hydrocarbon Receptor (AHR), a receptor whose activation has been
101
involved in the toxicity induced by dioxin and other industrial chemicals. Interestingly, the cardiotoxicity of these chemicals is probably related to the presence of the AHR in the heart (29, 30). Although it is rather speculative, this view may open new insights into that complex issue, in particular to explain the mechanism through which resveratrol is cardioprotective. Coming back now to nutrition, it is important to remember that resveratrol is a phytoalexin, existing in cis and trans configuration in a variety of spermatophyte plants including eucalyptus, peanuts and grapes. Resveratrol is present, sometimes in large amounts, in some wines (essentially red wines). In contrast with most other flavonoids, it is absent from non-alcoholic beverages because it is not water-soluble. Its presence in nuts (especially peanuts) corroborates the theory (essentially supported by the results of epidemiological studies) that the consumption of nuts is also associated with a low rate of cardiovascular disease mortality (31). The mechanism through which nuts (in particular peanuts that have the particularity not to be rich in omega-3 fatty acids as compared with walnuts) protect against CHD has not been fully clarified once the protective effect of omega-3 fatty acids have been taken into account. Why are the nuts lacking omega-3 fatty acids protective? One possibility, at least for peanuts, is their richness in resveratrol. Thus, in addition to its chemopreventive activity against cancer (32, 33) and to the modulation of prostaglandin synthesis (34), resveratrol may be a major cardioprotective nutrient, at least when it is associated with ethanol in wine or other unsaturated fatty acids in nuts. As underlined by Savouret et al (28), resveratrol is indeed a major component of the Mediterranean diet (as wine and nuts are) and is probably one of the factors explaining the French paradox (35). The lesson that we should draw from the resveratrol issue (as also illustrated by the article of Savouret et al) is that the protective effect induced by the consumption of one single nutrient may be mediated through several different mechanisms. Resveratrol is a potent antioxidant; it interferes with the prostaglandin and the NOS pathways and, according to the theory proposed by Savouret et al (28), it may have a direct protective effect on several organs other than the heart by antagonizing the activation of AHR. The central (converging) point of these different effects, however, may be the myocardium. Further studies are warranted to investigate the many questions risen by this theory. The study of myocardial ischemia in patients is a difficult task. Carefully conducted animal studies are
102
required before we can test a new nutrition-based theory in clinical trials. This is one of the beautiful aspects of future experimental cardiology.
References 1 Pearson TA (1996) Alcohol and heart disease. Circulation 94: 3023-3025 2. Rimm EB, Glovannuccl EL, Wdlett WC, et al (1991) Prospective study of alcohol consumption and risk of coronary disease in men. Lancet 338. 464-468 3. Stampfer MJ, Colditz GA, Willett WC, et al (1988) A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 319:267-273 4. Camargo CA, Hennekens CH, Gaziano JM. et al (1997) Prospective study of moderate alcohol consumption and mortality in US male physicians. Arch Intern Med 157' 79-85 5. D1 Castelnuovo A, Rotondo S, Iacoviello L, et al (2002) Metaanalysis of wine and beer consumption in relation to vascular risk. Circulation 105' 2836-2844 6. Gronbaek M, Dels A, Sorensen T, et al (1995) Mortality associated with moderate intakes of wine, beer, or spirits. BMJ 310: 1165-1169. 7. Gazlano JM, Gazlano TA, Glynn RJ, et al (2000) Light-to-moderate alcohol consumption and mortality in the Physicians' Health Study enrollment cohort. J Am Coll Cardiol 35' 96-105. 8. Thun MJ, Peto R, Lopez AD, et al (1997) Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med 337:1705-1714 9. Rimm EB, Fosher K, Crlqui M, et al (1999) Moderate alcohol intake and lower risk of coronary heart disease: meta-analysls of effects on llplds and haemostatic factors. BMJ 319:1523-1528 10. Renaud S, de Lorgeri1 M (1992) Wine, alcohol, platelets aggregation and the French Paradox for coronary heart disease. Lancet 339' 1523-1526 11. de Lorgeril M, Salen P (1999) Wine ethanol, platelets, and Mediterranean diet. Lancet 353:1067 12. Muntwyler J, Hennekens CH, Burlng JE, et al (1998) Mortality and light to moderate alcohol consumption after myocardial infarction. Lancet 352:1882-1885 13. Mukamal KJ, Maclure M, Muller JE, et al (2001) Prior alcohol consumption and mortality following acute myocardial infarction JAMA 285' 1965-1970 14 de Lorgeril M, Salen P, Martin JL, etal (2002) Wine drinking and risks of cardiovascular complications after recent acute myocardial infarction. Circulation 106:1465-1469 15. Albert CM, Manson JE, Cook NR et al (1999) Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians. Circulation 100:944-950
M. de Lorgenl, etal
16. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in lschermc myocardium. Circulation 74:1124-1136 17. Mlyamae M, Diamond I, Welner MW, et at (1997) Regular alcohol consumption mimics cardiac preconditioning by protecting against lschemia-reperfuslon injury. Proc Natl Acad Scl USA 94: 3235-3239 18. Zhou HZ, Karliner JS, Gray MO (2002) Moderate alcohol consumption induces sustained cardiac protection by activating PKC-epsilon and Akt. AJP- Heart and Circulatory Physiology 283' H165-H174 19. Chen CH, Gray MO, Mochly-Rosen D (1999) Cardloprotection from lschemia by a brief exposure to physiological levels of ethanol: role of epsilon protein klnase C. Proc Natl Acad Sci USA 96:12784-12789 20. Pagel PS, Toiler WG, Gross ER, et al (2000) KATpchannel mediate the beneficial effects of chronic ethanol ingestion. AJP-Heart and Circulatory Physiology 279:H2574-H2579 21 Krenz M, Baines CP, Yang XM, et al (2001) Acute ethanol exposure fails to elicit preconditioning m situ rabbit hearts because of its continued presence during lschemia. J Am Coil Cardlol 37: 601-607 22. Ross JA, Kasum CM (2002) Dietary flavonolds, bioavailability, metabolic effects, and safety. Annu Rev Nutr 22:19-34 23. Pataki T, Bak I, Kovacs P, et al (2002) Grape seed proanthocyanidins improved cardiac recovery during reperfuslon after ischemia In isolated rat hearts. Am J Clin Nutr 75:894-899 24. Hattorl R, Otani H, Maullk N, Das D (2002) Pharmacological precondltlomng with resveratrol: role of nitric oxide. Am J Physlol Heart Circ Physiol 282:H1988-H1995 25. Imamura G, Bertelli A, Bertelli A, et al (2002) Pharmacological precondltlonlong with resveratrol: an insight with iNOS knockout mice. Am J Physiol Heart Circ Physlol 282:H1996-H2003 26. Wallerath T, Deckert G, Ternes T, et al (2002) Resveratrol, a polyphenohc phytoalexln present in red wine. enhances expression and activity of endothelial nitric oxide synthase. Circulation 106:1652-1658 27. Bertella AA, Glovanmni L, Stradl R, et al (1998) Evaluation of kinetic parameters of natural phytoalexin in resveratrol orally administered in wine to rats. Drugs Exp Clln Res 24:51-55 28. Savouret JF, Berdeaux A, Casper RF (2003) The aryl hydrocarbon receptor and its xenobiotlc llgands: a fundamental trigger for cardiovascular diseases. Nutr Metab Cardiovasc Dis 13: 104-113 29. Heid SE, Walker MK, Swanson HI (2001) Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation. Toxicol Sci 61:187-196 30. Walker MK, Catron TF (2000) CharacterisatIon of cardlotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chemicals during early chick embryo development. Toxlcol Appl Pharmacol 167:210-221
Resveratrol in experimental cardiology
31. de Lorgeril M, Salen P, Laporte F, et al (2001) Potential use of nuts for the prevention and treatment of coronary heart disease: from natural to functional foods. Nutr Metab Cardiovasc Dis 11:362-371 32. Jang M, Cai L, Udeam GO, et al (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218-220 33. Bhat KP, Lantvlt D, Chrlstov K, et al. (2001) Estrogenic and antiestrogenlc properties of resveratrol in mammary tumor
103
models. Cancer Res 61:7456-7463 34. Moreno JJ (2000) Resveratrol modulates arachidonic acid release, prostaglandin synthesis, and 3T6 fibroblast growth. J Pharmacol Exp Ther 294. 333-338 35. de Lorgeril M, Salen P, Paillard F, et al (2002) Mediterranean diet and the French paradox: two distinct biogeographic concepts for one consolidated scientific theory on the role of nutrition in coronary heart disease. Cardiovasc Res 54. 503-515
Nutr Metab Cardlovasc Dis (2003) 13. 100-103
VIEWPOINT
Resveratrol and non-ethanolic components of wine in experimental cardiology M. de Lorgeril, P. Salen, A. Guiraud, E Boucher, and J. de Leiris Laboratolre du Stress Cardlovasculalre et Pathologies Assocl6es, Umverslt6 Joseph Fourier, Grenoble, France
Abstract The mechanisms through which the consumption of alcoholic beverages, in particular wine, protects against cardiac and vascular diseases remain largely unexplored. New methods are needed to investigate that crucial medical and scientific question. Several groups are now beginning to use animal models of myocardial ischemia and reperfusion to explore whether certam nutrients, including ethanol and non-ethanolic components of wine, may have a specific protective effect on the myocardium, independently from the classical risk factors involved in vascular atherosclerosis and thrombosis. Concepts used tn experimental cardiology, such as preconditioning and stunning, are now entering the field of nutritton, and this will undoubtedly lead to constderable improvements in the prevention and treatment of cardtovascular diseases. Nutr Metab Cardiovasc Dis (2003) 13:100-103 ~2003, Medlkal Press
A number of epidemaological studies have reported decreased cardiovascular mortality and morbidity among moderate alcohol drinkers as compared with abstainers (1-8). Considerable controversy has arisen regarding the mechanisms that may be responsible for alcohol-induced cardiac protection, and several different mechanisms have been suggested. These include an effect on blood liplds and platelets resulting in a decreased rate of atherosclerotic and thrombotic coronary artery obstruction (9-11). However, other
Key-words Resveratrol, ethanol, non-ethanohc components of wine, experimental cardiology Correspondence to M de Lorgerll, Laboratolre du Stress Cardaovasculalreet Pathologies Assocl6es, UFR de M6declne et Pharmacle, Domalne de la Merci, 38706 La Tronche (Grenoble), France E-mad mlchel.delorgenl@ulf-grenoble fr
mechanisms are probably involved. For instance, recent studies have shown that moderate drinking may improve early outcomes after acute myocardial infarction and may prevent sudden cardiac death (12-15), which suggests a direct protective effect on the myocardium. Thus, regular ethanol consumption may mimic the classical ischemic preconditioning (IPC) and protect against ischemia and repeffusion injury. What is IPC? IPC is a phenomenon in which single or multiple brief periods of ischemia have been shown to protect the heart against a more prolonged ischemic insult, thus resulting in a marked reduction in myocardial infarct size, the severity of stunning, or the incidence of ventricular arrhythmias (16). All these consequences are potentially important in the clinical settings. Many groups have tried and are still trying to understand the mechanisms of IPC in order to design new pharmacological approaches (and to market new drugs) for the treatment and prevention of coronary heart disease (CHD). Despite a lot of brilliant and optimistic publications in that field (in particular those related to the protective effect of antioxidant, anti-leukocyte and anti-inflammatory compounds during reperfusion) over the past twenty years, one may reasonably say that this experimental approach has been rather disappointing. No major drug based on the concept of IPC has emerged for clinical use. One major exception, however, is the discovery that ethanol drinking may mimic IPC. In fact, several groups have reported that ethanol protects the heart against ischemia and reperfusion injury (17-21). On the other hand, beside the cardioprotective effect of ethanol itself, non-ethanolic components of wine may be involved in the protection resulting from their consumption, at least when taken in moderate amounts. As regards these components, in contrast with alcoholic beverages in general, there are only a few clinical or epidemiological data to support that assumption. For instance, studies sup-
Resveratrol in experimental cardiology
port a protective effect of fiavonoids, especially when taken with tea or wine (22). However, no human trial has been designed so far to test these compounds, which are probably responsible for the antioxidant activity of wine. The beneficial effect of wine drinking has been attributed, at least partly, to the antioxidants present in its polyphenol fraction, which include catechin, proanthocyanidins and resveratrol. It is noteworthy that grape seed proanthocyanidins were actually shown to have cardiac protective effects against reperfusion-induced injury in a rat model of myocardial ischemia, via their ability to reduce or remove, directly or indirectly, free radicals in the myocardium being reperfused after ischemia (23). Further studies are however required to confirm these interesting data. On the other hand, resveratrol, a naturally occurring phenolic compound found in great amounts in grape skins and in wines, has been found to protect the heart from ischemiareperfusion injury (24). Preconditioning of the heart with resveratrol resulted in both reduced infarct size and improved postischemic ventricular functional recovery. This is an important point because IPC in the rat model has never been associated with a beneficial effect on postischemic left ventricular function. It was hypothesized that resveratrol could pharmacologically precondition the heart in a nitric oxide (NO)-dependent manner. As a matter of fact, resveratrol was unable to precondition inducible NO synthase (iNOS) knockout mouse heart, whereas it could successfully precondition wild-type mouse hearts, which indicates an essential role of iNOS in cardiac resveratrol preconditioning (25). In fact, using cultured human vein endothelial cell, resveratrol was also shown to up-regulate endothelial NOS mRNA expression in a time- and concentration-dependent manner (26). Resveratrol also enhanced the production of bioactive NO and increased the activity of the endothelial NOS gene promoter (26). All these data suggest, but do not prove, that resveratrol may protect the heart by acting on the endothelial NOS. In addition, it was shown that a reasonable consumption of certain resveratrol-rich wines results in a significant accumulation of that lipophilic substance in tissues such as the heart and the kidneys (27). Thus, the preconditioning effect of resveratrol may be dependent of its presence in situ. One point that remains to explain is what is the molecular target of resveratrol in the myocardium. In the article published in the current issue of NMCD (28), Savouret et al propose that resveratrol is a ligand (with antagonistic abilities) of the Aryl Hydrocarbon Receptor (AHR), a receptor whose activation has been
101
involved in the toxicity induced by dioxin and other industrial chemicals. Interestingly, the cardiotoxicity of these chemicals is probably related to the presence of the AHR in the heart (29, 30). Although it is rather speculative, this view may open new insights into that complex issue, in particular to explain the mechanism through which resveratrol is cardioprotective. Coming back now to nutrition, it is important to remember that resveratrol is a phytoalexin, existing in cis and trans configuration in a variety of spermatophyte plants including eucalyptus, peanuts and grapes. Resveratrol is present, sometimes in large amounts, in some wines (essentially red wines). In contrast with most other flavonoids, it is absent from non-alcoholic beverages because it is not water-soluble. Its presence in nuts (especially peanuts) corroborates the theory (essentially supported by the results of epidemiological studies) that the consumption of nuts is also associated with a low rate of cardiovascular disease mortality (31). The mechanism through which nuts (in particular peanuts that have the particularity not to be rich in omega-3 fatty acids as compared with walnuts) protect against CHD has not been fully clarified once the protective effect of omega-3 fatty acids have been taken into account. Why are the nuts lacking omega-3 fatty acids protective? One possibility, at least for peanuts, is their richness in resveratrol. Thus, in addition to its chemopreventive activity against cancer (32, 33) and to the modulation of prostaglandin synthesis (34), resveratrol may be a major cardioprotective nutrient, at least when it is associated with ethanol in wine or other unsaturated fatty acids in nuts. As underlined by Savouret et al (28), resveratrol is indeed a major component of the Mediterranean diet (as wine and nuts are) and is probably one of the factors explaining the French paradox (35). The lesson that we should draw from the resveratrol issue (as also illustrated by the article of Savouret et al) is that the protective effect induced by the consumption of one single nutrient may be mediated through several different mechanisms. Resveratrol is a potent antioxidant; it interferes with the prostaglandin and the NOS pathways and, according to the theory proposed by Savouret et al (28), it may have a direct protective effect on several organs other than the heart by antagonizing the activation of AHR. The central (converging) point of these different effects, however, may be the myocardium. Further studies are warranted to investigate the many questions risen by this theory. The study of myocardial ischemia in patients is a difficult task. Carefully conducted animal studies are
102
required before we can test a new nutrition-based theory in clinical trials. This is one of the beautiful aspects of future experimental cardiology.
References 1 Pearson TA (1996) Alcohol and heart disease. Circulation 94: 3023-3025 2. Rimm EB, Glovannuccl EL, Wdlett WC, et al (1991) Prospective study of alcohol consumption and risk of coronary disease in men. Lancet 338. 464-468 3. Stampfer MJ, Colditz GA, Willett WC, et al (1988) A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med 319:267-273 4. Camargo CA, Hennekens CH, Gaziano JM. et al (1997) Prospective study of moderate alcohol consumption and mortality in US male physicians. Arch Intern Med 157' 79-85 5. D1 Castelnuovo A, Rotondo S, Iacoviello L, et al (2002) Metaanalysis of wine and beer consumption in relation to vascular risk. Circulation 105' 2836-2844 6. Gronbaek M, Dels A, Sorensen T, et al (1995) Mortality associated with moderate intakes of wine, beer, or spirits. BMJ 310: 1165-1169. 7. Gazlano JM, Gazlano TA, Glynn RJ, et al (2000) Light-to-moderate alcohol consumption and mortality in the Physicians' Health Study enrollment cohort. J Am Coll Cardiol 35' 96-105. 8. Thun MJ, Peto R, Lopez AD, et al (1997) Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med 337:1705-1714 9. Rimm EB, Fosher K, Crlqui M, et al (1999) Moderate alcohol intake and lower risk of coronary heart disease: meta-analysls of effects on llplds and haemostatic factors. BMJ 319:1523-1528 10. Renaud S, de Lorgeri1 M (1992) Wine, alcohol, platelets aggregation and the French Paradox for coronary heart disease. Lancet 339' 1523-1526 11. de Lorgeril M, Salen P (1999) Wine ethanol, platelets, and Mediterranean diet. Lancet 353:1067 12. Muntwyler J, Hennekens CH, Burlng JE, et al (1998) Mortality and light to moderate alcohol consumption after myocardial infarction. Lancet 352:1882-1885 13. Mukamal KJ, Maclure M, Muller JE, et al (2001) Prior alcohol consumption and mortality following acute myocardial infarction JAMA 285' 1965-1970 14 de Lorgeril M, Salen P, Martin JL, etal (2002) Wine drinking and risks of cardiovascular complications after recent acute myocardial infarction. Circulation 106:1465-1469 15. Albert CM, Manson JE, Cook NR et al (1999) Moderate alcohol consumption and the risk of sudden cardiac death among US male physicians. Circulation 100:944-950
M. de Lorgenl, etal
16. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in lschermc myocardium. Circulation 74:1124-1136 17. Mlyamae M, Diamond I, Welner MW, et at (1997) Regular alcohol consumption mimics cardiac preconditioning by protecting against lschemia-reperfuslon injury. Proc Natl Acad Scl USA 94: 3235-3239 18. Zhou HZ, Karliner JS, Gray MO (2002) Moderate alcohol consumption induces sustained cardiac protection by activating PKC-epsilon and Akt. AJP- Heart and Circulatory Physiology 283' H165-H174 19. Chen CH, Gray MO, Mochly-Rosen D (1999) Cardloprotection from lschemia by a brief exposure to physiological levels of ethanol: role of epsilon protein klnase C. Proc Natl Acad Sci USA 96:12784-12789 20. Pagel PS, Toiler WG, Gross ER, et al (2000) KATpchannel mediate the beneficial effects of chronic ethanol ingestion. AJP-Heart and Circulatory Physiology 279:H2574-H2579 21 Krenz M, Baines CP, Yang XM, et al (2001) Acute ethanol exposure fails to elicit preconditioning m situ rabbit hearts because of its continued presence during lschemia. J Am Coil Cardlol 37: 601-607 22. Ross JA, Kasum CM (2002) Dietary flavonolds, bioavailability, metabolic effects, and safety. Annu Rev Nutr 22:19-34 23. Pataki T, Bak I, Kovacs P, et al (2002) Grape seed proanthocyanidins improved cardiac recovery during reperfuslon after ischemia In isolated rat hearts. Am J Clin Nutr 75:894-899 24. Hattorl R, Otani H, Maullk N, Das D (2002) Pharmacological precondltlomng with resveratrol: role of nitric oxide. Am J Physlol Heart Circ Physiol 282:H1988-H1995 25. Imamura G, Bertelli A, Bertelli A, et al (2002) Pharmacological precondltlonlong with resveratrol: an insight with iNOS knockout mice. Am J Physiol Heart Circ Physlol 282:H1996-H2003 26. Wallerath T, Deckert G, Ternes T, et al (2002) Resveratrol, a polyphenohc phytoalexln present in red wine. enhances expression and activity of endothelial nitric oxide synthase. Circulation 106:1652-1658 27. Bertella AA, Glovanmni L, Stradl R, et al (1998) Evaluation of kinetic parameters of natural phytoalexin in resveratrol orally administered in wine to rats. Drugs Exp Clln Res 24:51-55 28. Savouret JF, Berdeaux A, Casper RF (2003) The aryl hydrocarbon receptor and its xenobiotlc llgands: a fundamental trigger for cardiovascular diseases. Nutr Metab Cardiovasc Dis 13: 104-113 29. Heid SE, Walker MK, Swanson HI (2001) Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation. Toxicol Sci 61:187-196 30. Walker MK, Catron TF (2000) CharacterisatIon of cardlotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chemicals during early chick embryo development. Toxlcol Appl Pharmacol 167:210-221
Resveratrol in experimental cardiology
31. de Lorgeril M, Salen P, Laporte F, et al (2001) Potential use of nuts for the prevention and treatment of coronary heart disease: from natural to functional foods. Nutr Metab Cardiovasc Dis 11:362-371 32. Jang M, Cai L, Udeam GO, et al (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218-220 33. Bhat KP, Lantvlt D, Chrlstov K, et al. (2001) Estrogenic and antiestrogenlc properties of resveratrol in mammary tumor
103
models. Cancer Res 61:7456-7463 34. Moreno JJ (2000) Resveratrol modulates arachidonic acid release, prostaglandin synthesis, and 3T6 fibroblast growth. J Pharmacol Exp Ther 294. 333-338 35. de Lorgeril M, Salen P, Paillard F, et al (2002) Mediterranean diet and the French paradox: two distinct biogeographic concepts for one consolidated scientific theory on the role of nutrition in coronary heart disease. Cardiovasc Res 54. 503-515