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    Wednesday, February 25, 2009

    Experimental Evidence for the Cardioprotective Effects of Red Wine

    Samarjit Das, BSc, Dev D Santani, PhD, and Naranjan S Dhalla, PhD MD (Hon) DSc (Hon)
    Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Correspondence: Dr Naranjan S Dhalla, Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, 351 Tache Avenue, Winnipeg, Manitoba R2H 2A6. Telephone 204-235-3417, fax 204-233-6723, e-mail

    Received March 9, 2006; Accepted March 20, 2006.


    Both epidemiological and experimental studies have revealed that intake of wine, particularly red wine, in moderation protects cardiovascular health; however, the experimental basis for such an action is not fully understood. Because all types of red wine contain varying amounts of alcohol and antioxidants, it is likely that the cardioprotective effect of red wine is due to both these constituents. In view of its direct action on the vascular smooth muscle cells, alcohol may produce coronary vasodilation in addition to attenuating oxidative stress by its action on the central nervous system. The antioxidant components of red wine may provide cardioprotection by their ability to reduce oxidative stress in the heart under different pathological conditions. Mild-to-moderate red wine consumption improves cardiac function in the ischemic myocardium through the protection of endothelial function, the expression of several cardioprotective oxidative stress-inducible proteins, as well as the activation of adenosine receptors and nitrous oxide synthase mechanisms.

    The beneficial effects of wine can be traced back to the dawn of human civilization. It is a global socioreligious symbol associated with a multitude of therapeutic benefits, including medicinal as well as magical powers. The current popular propositions about the benefits of ‘moderate wine drinking’ in fact date back through history, and were first proposed by the Father of Medicine, Hippocrates of Kos, in Greece. However, the cardiovascular benefits of red wine became the hub of research activity after the observation of ‘French paradox’ by Renaud and de Lorgeril (1) who, in 1992, found that there was a low mortality rate from ischemic heart disease among French people despite their high consumption of saturated fats and the prevalence of other risk factors, such as smoking. This was attributed to their so-called ‘Mediterranean diet’, which includes a large intake of wine. In 1997, a Dutch epidemiological study (2) showed that coronary artery disease in elderly men is inversely proportional to their flavonoids intake.

    There is evidence from different sources showing that oxidative stress disturbs the normal balance between the pro-oxidants (oxygen free radicals) and antioxidants either by increasing the formation of free radicals or by decreasing the amount of antioxidants in the myocardium. This oxidative stress plays an important role in cardiovascular diseases, such as ischemic heart disease, arteriosclerosis, congestive heart failure, cardiomyopathy, hypertrophy and arrhythmias (3). Several studies highlight the role of free radicals in myocardial ischemic reperfusion injury (4–6). These studies indicate that the antioxidant reserve and antioxidant enzymes are significantly reduced during ischemia-reperfusion injury. Palm oil-derived polyphenols, such as the mixture of alpha (α), beta (β), gamma (γ) and delta (δ) tocotrienols, as well as tocopherols, have also been shown to significantly reduce the injury caused by ischemia and/or reperfusion through their ability to stabilize proteasomes (7). During ischemia and/or reperfusion injury, there is loss of antioxidant enzymes and antioxidants and thus, the overall antioxidant reserve of the heart is reduced. One of the major functions of antioxidants is to block free radical formation. In the present report, we provide evidence for the cardioprotective effects of red wine and two of its constituents: alcohol and polyphenolic compounds, especially 3,4′,5-trihydroxy-trans-stilbene (resveratrol) and proanthocyanidins.

    What is in Red Wine That Affects The Cardiovascular System?

    Red wine is rich in a variety of polyphenolic compounds. These compounds are responsible for the colour, bitterness and astringent taste, and act as preservatives that allow for the long aging process used in the manufacturing of wine. These potent antioxidants are found in the solid components of grape berries, such as the skin and seeds. Polyphenols in general are characterized as flavonoids and nonflavonoids: of the flavonoids – catechin, quercetin, proanthocyanidins, condensed tannins and anthocyanins; of the nonflavonoids –hydrolysable tannins, benzene and cinnamate derivatives (8) are found in red wine. Red wine is produced by fermenting grape juice with the pulp, whereas white wine is produced by fermenting grape juice in the absence of the grape pulp. As a result, red wine has a much higher polyphenol content than white wine, as well as a higher level of antioxidant activity (9,10). Besides polyphenols, alcohol constitutes up to 15% of the volume of red wine (Figure 1). A number of epidemiological studies have shown an inverse relationship between moderate alcohol consumption and coronary artery disease; however, high consumption of alcohol leads to increased morbidity and mortality, thus following a J-shaped curve (11–24).

    Figure 1
    Red wine and its various components protect the heart from ischemia and/or reperfusion injury as well as attenuate atherosclerosis.

    Red wine polyphenols act as antioxidants

    Arteriosclerosis accounts for almost 40% of all mortality in the United States. According to the oxidative theory, the process of atherogenesis is accelerated by oxidation of low-density lipoprotein (LDL) (25–30). There are a number of biological mechanisms that could lead to LDL oxidation. For instance, oxidation of LDL polyunsaturated lipid components occurs with reactive free radicals and enzyme systems, such as 15-lipoxygenase, cytochrome p450 and myeloperoxidase (31). Red wine polyphenols can reduce LDL sensitivity to lipid peroxidation. In a study (31) in which subjects consumed 375 mL/day of red wine for two weeks, lipid peroxides decreased by 40%, thiobarbituric acid reactive substances by 44% and conjugated dienes by 48%. This study also suggested a pro-oxidant effect of white wine because there was a 21% to 28% increase in thiobarbituric acid reactive substances in the subjects who consumed white wine. Fermenting white wine along with the grape pulp and solids increased its ability to scavenge free radicals and inhibit LDL’s copper ion-induced oxidation. Oxidation properties of this wine were inhibited by up to 87% when the grape juice was allowed to ferment for an additional 18 h resulting in 18% alcohol. The increased inhibition is due to the increased polyphenolic content and is similar to the 94% inhibition seen with red wines (25). Thus, it was demonstrated that it is red wine and not white wine that has important antioxidant activity because of the higher polyphenolic concentration. In another study (32), an alcohol-free powder of red wine phenolic extract was shown to have similar effects as red wine, acting as an antioxidant both in plasma and on LDL. From this study, it can be inferred that the cardioprotective effects of red wine are mainly through its polyphenolic compounds.

    The antioxidant effects of red wine polyphenols may result from several mechanisms. Polyphenols can act as free radical scavengers by acting as reducing agents or as hydrogen atom-donating molecules. Chelation of transition metal ions by polyphenols can also diminish the capacity of the metal to generate free radicals (31). Furthermore, reactive copper ion has been found in atherosclerotic plaques and in ceruloplasmin and therefore has been suggested to cause oxidation of LDL (33), whereas polyphenols have been found to strongly inhibit oxidation induced by copper more than that induced by aqueous peroxyls (34). Polyphenols have also been found to reduce macrophage oxidative stress through the inhibition of NADPH oxidase, 15-lipoxygenase, cytochrome p450 and myeloperoxidase (31). Red wine polyphenols are absorbed efficiently in human subjects and bind to LDL, thus protecting it from oxidation (31,32,35). Resveratrol also reduces the synthesis of lipids and eicosanoids, which promote inflammation and atherosclerosis. In another study (36), it was demonstrated that during the digestive process, the action of gastric juice on foodstuffs produces hydroperoxides and malonaldehyde. These free radicals co-oxidized vitamin E, β-carotene and vitamin C, but the lipid peroxidation and co-oxidation of vitamin E and β-carotene were inhibited by red wine polyphenols at acidic pH conditions of the stomach. It was also shown that in the presence of catechin, a well-known polyphenol found in red wine, ascorbic acid worked synergistically to prevent lipid peroxidation and β-carotene co-oxidation (36).

    Red wine affects high-density lipoprotein

    Red wine is capable of increasing high-density lipoprotein (HDL). This lipid molecule is required for the transport of cholesterol from the arteries and various parts of the body back to the liver for its metabolism and excretion. Therefore, HDL is protective against arteriosclerosis. According to several studies (12,32,37,38), alcohol consumption increases the levels of HDL and thus, may explain a part of red wine’s protective effect. Some studies have shown that moderate consumption of ethanol by itself can increase the plasma concentrations of HDL (39). In a study (35) in which healthy men received 400 mL/day of wine for two weeks, an increase in HDL was found with consumption of red wine although no such beneficial increase was found with white wine. Several studies have shown a dose-dependent increase in HDL and in apolipoprotein A-I levels (37,40). The Enquete Cas-Temoins de L’Infarctus du Myocarde (ECTIM) study (40) involved 561 men with myocardial infarction and 463 healthy men from France and Northern Ireland. It was concluded that there was a significant increase in HDL cholesterol – from 0.47 g/L to 0.59 g/L – in men who consumed 2.3 ounces/day of alcohol as compared with nondrinkers. These men consumed mostly red wine. They also reported an increase in apolipoprotein A-I and A-II (40). In another study (37), it was found that HDL levels increased in people consuming 1.7 ounces/day of wine. Isolated HDL showed an increase of 27% in all molecular species of cholesteryl esters. This effect was also associated with enrichment of the HDL particles in polyunsaturated phospholipids, especially those containing arachidonic acids (+30%) and eicosapentaenoic acids (+90%) and those containing omega-3 fatty acids, which are said to be beneficial against coronary artery disease.

    Red wine inhibits vascular smooth muscle cell proliferation and migration

    Vascular smooth muscle cell (SMC) proliferation and migration is an important component of atherogenesis (16,41). The abnormal proliferation of vascular SMC in the arterial intima is also an important step in the pathology of restenosis (41). In a rabbit endothelial denudation model, rabbits fed a high-dose resveratrol diet (4 mg/kg/day) developed less intimal hyperplasia than that of control rabbits. The number of SMCs in the thickened intima was reduced in the resveratrol-treated animals (42). In another study (16), bovine aortic SMCs were treated with growth media supplemented with dealcoholized red wine, red wine, or polyphenol extract or resveratrol for 48 h. It was observed that red wine and red wine polyphenols inhibited SMC proliferation in a dose-dependent manner. There are several mechanisms by which red wine could inhibit vascular SMC proliferation. For instance, platelet-derived growth factor is a potent chemo-attractant for SMCs. It induces cellular motility by activation of the phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase pathways (26). It has been shown that red wine polyphenols inhibit platelet-derived growth factor and serum SMC migration through the inhibition of these signalling pathways (43). Another red wine flavonoid, quercetin, is also said to have antiatherogenic effects on vascular SMCs by inhibiting matrix metallopro-teinase-9, which is responsible for development of intimal formations and plaque rupture in atherogenic lesions (44). Resveratrol has also been shown to inhibit the expression of cell adhesion molecules intracellular cell adhesion molecule 1 (ICAM 1) and vascular cell adhesion molecule 1 (VCAM 1) on the endothelium (45), thus bringing about a reduction in monocyte and granulocyte adhesion.

    Red wine polyphenols attenuate platelet aggregation

    Many cardioprotective drugs, such as acetylsalicylic acid, act by attenuating platelet aggregability (46). Polyphenols, specifically resveratrol and quercetin, have an antiaggregability effect on human platelets (47). It has also been shown that aggregation in response to ADP and thrombin in human platelets is strongly inhibited by red wine (48). Quercetin has also been demonstrated to decrease the platelet activity by decreasing platelet cytosolic calcium as a consequence of increased cyclic GMP phosphodiesterase activity (47). In a human study (49), subjects who had 375 mL/day of red wine for two to four weeks had decreased ADP-induced platelet aggregation. Red wine, administered intravenously or intra-gastrically at a dose of 1.6 mL/kg and 4.0 mL/kg in stenosed canine coronary arteries, reduced the cyclic blood flow reductions caused by periodic formation of acute platelet-mediated thrombi (46). These same effects were observed when high quantities of grape juice were given, but not with white wine, thus suggesting a role for red wine polyphenols for this attenuation in platelet aggregation (46). Moderate consumption of ethanol by itself is shown to decrease the adhesiveness of platelets (39).

    Cardioprotective effects of red wine, resveratrol and proan-thocyanidins

    Red wine is composed of more than 500 compounds although only a few are present at concentrations of more than 100 mg/L. These include water, glycerol, ethanol, sugar and organic acids. There is increasing evidence supporting the cardioprotective effects of ethanol (Figure 2), although the mechanisms of cardioprotection remain somewhat obscure. Ethanol decreases sympathetic activity, thereby decreasing heart rate and cardiac contraction while inducing coronary vasodilation; all these effects lead to cardioprotection. On the other hand, Grassi et al (50) showed that increased plasma ethanol level significantly elevates the blood pressure, heart rate and sympathetic nerve activity. Low to moderate concentrations of ethanol are shown to inhibit coronary muscle contraction, increase coronary flow and improve the cardiac output (51). The mechanisms by which ethanol is a vasodilator are still unknown, however, a study on the effects of changes in extracellular Ca2+ on muscle contractions supports a view that ethanol directly activates the coronary vascular smooth muscle by modulating Ca2+ metabolism. The decrease in muscle contraction can arise from decreases in Ca2+ influx through voltage-dependant and receptor-operated Ca2+ channels in the sarcolemmal membrane as well as a decrease in Ca2+ release from the sarcoplasmic reticulum. This impaired intracellular availability of Ca2+ may be responsible for ethanol’s vasodilating effect. As a result, ethanol dilates the coronary arteries and increases the coronary flow. The increased coronary flow improves nutrient and oxygen delivery to the myocardium, maintaining normal cardiac cellular metabolism under stressful situations and resulting in cardioprotection (Figure 3). Other possible causes for the vasodilating effects of ethanol, including changes in cardiac metabolism and generation, as well as release of some intermediate vasodilator vasoactive substance (52), cannot be ruled out. In another study (53), ethanol was found to have cardio-protective effects against ischemia-reperfusion. Low to moderate concentrations of ethanol were shown to significantly increase oxidative stress in the heart. During the first 12 h, malondialdehyde levels in ethanol-perfused hearts increased significantly but decreased after 24 h and returned to baseline levels after 72 h. Ethanol has been shown to induce the expression of the cardioprotective heat shock proteins (HSP), such as HSP-70 and HSP-90 (52,53). These findings suggest that ethanol initially induces oxidative stress, which is then translated into oxidative stress-inducible proteins. Ethanol was also found to inhibit the production of pro-apoptotic factors c-Jun and JNK-1 (53). Miyamae et al (54) showed that ethanol protects the heart from ischemia and/or reperfusion injury by adenosine signalling in guinea pigs. In rats, ethanol also creates ischemic preconditioning which may be mediated predominantly by α1-adrenergic signalling (54).

    Figure 2
    Proposed events for ethanol-induced cardioprotection.

    Figure 3
    Molecular mechanisms of the effect of ethanol leading to cardioprotection where sarcolemmal membrane and Ca2+ play an important role.

    Red wine is considered to exert cardioprotective effects due to the presence of different agents that exhibit antioxidant properties (Figure 4). The concentration of polyphenolic compounds in red wine is approximately 1800 mg/L to 3000 mg/L (55). Of the many polyphenolic compounds in red wine, resveratrol is found to be more cardioprotective. Grape plants do not synthesize resveratrol regularly. It is a defensive molecule, a phyto-alexin, produced to prevent the attack by pathogenic organisms and combat environmental stresses. Recently, a number of studies (56–58) have demonstrated that resveratrol given before ischemic arrest could protect the heart from ischemia and/or reperfusion injury. The role of nitric oxide (NO) is found to be one of the important mechanisms of pharmacological preconditioning by resveratrol (59,60). A recent study (59) suggested that the coordinated up-regulation of inducible NO synthase, vascular endothelial growth factor, kinase insert domain-containing receptor and endothelial NO synthase is one of the resveratrol preconditioning mechanisms. Another study (57) indicated that adenosine receptors have an important function in the resveratrol preconditioning. It suggested that adenosine A1 and A3 receptors, but not A2a or A2b receptors, play a critical role in the pharmacological preconditioning by resveratrol. Resveratrol likely activates both adenosine A1 and A3 receptors, which phosphorylates PI3K, which in turn phosphorylates protein kinase B (Akt), and thus preconditions the heart by producing NO as well as by the activation of antioxidant transcription factor BCl-2. Das et al (58) showed that the activation of adenosine A3 receptors can also precondition the heart by survival signal through the cyclic AMP response element-binding protein phosphorylation via PI3K-Akt and via mitogen-activated extracellular signal-regulated protein kinase-cyclic AMP response element-binding protein pathways. In another study (61), heme oxygenase-I has been reported to play an important role in resveratrol preconditioning. Resveratrol attenuates various soluble intercellular cytokines like ICAM, VCAM and E-selectin through improvement in the endothelium function, which reduces the infarct size (45). Apart from the redox signalling mechanism, resveratrol also protects the heart as a potent antioxidant by scavenging free radicals and inhibiting lipid peroxidation both in vitro and in vivo (53). Thus, resveratrol inhibits apoptotic cell death as well as release and/or generation of inflammatory mediators. Some of the mechanisms for the cardioprotective effects of resveratrol are depicted in Figures 5 and 6.

    Figure 4
    Some major polyphenols and flavonoids in red wine which protect the heart.

    Figure 5
    The cardioprotective effect of resveratrol by scavenging oxyradicals.

    Figure 6
    Improvement of endothelium function by resveratrol that ultimately leads to cardioprotection. sICAM Soluble intracellular cell adhesion molecule; sVCAM Soluble vascular cell adhesion molecule.

    Proanthocyanidin, a known flavonoid, is one of the key components found to be cardioprotective in red wine. Proanthocyanidin acts as a potent antioxidant by scavenging both peroxyl and hydroxyl radicals (62), and thus provides protection against myocardial ischemia-reperfusion injury, ventricular fibrillation, ventricular tachycardia and cardiomyocyte apoptosis (63). Proanthocyanidin inhibits cardiomyocyte apoptosis, and downregulates some of the pro-apoptotic genes c-JUN and JNK-1 (64). In another study, Sato et al (62) demonstrated that proanthocyanidin-fed rats showed better post-ischemic ventricular recovery and reduced myocardial infarction compared with those of the control group. A more recent study on chick cardiomyocytes has revealed the effect of proanthocyanidin on reactive oxygen species generation, cell survival, lactate dehydrogenase release and caspase-3 activity (65).

    Red wine polyphenols affect vasomotor tone

    Red wine polyphenol cardioprotective effects can be seen through various mechanisms. As discussed earlier, polyphenols act as antioxidants. Resveratrol, in particular, improves endothelium function by inhibiting the expression of ICAM and VCAM (45). Also, endothelial NO has vasodilatory effects and therefore is said to be vasoprotective and antiathero-sclerotic (66). Resveratrol can upregulate eNOS expression and consequently increase eNOS-derived NO production. This was observed in an in vitro study (67) when human umbilical vein endothelial cells were incubated for 24 h to 72 h with 10 μmol/L of resveratrol or in the culture medium containing wine. An enhanced endothelial-dependent NO-mediated vasorelaxation was observed (67). When human umbilical vein endothelial cells were exposed to 7.4 μmol/L of resveratrol, eNOS mRNA expression increased by approximately 150%; red wine increased it by 230% compared with the levels in the controls. Because quercetin was found to produce a marked coronary vasorelaxation effect that is endothelial independent, it can be concluded that resveratrol is not the only component responsible for red wine’s vasorelaxation effects. Ethanol is thought to increase polyphenol availability by improving its intestinal absorption, delaying excretion or by affecting its flow through the xenobiotic excretion pathways (39).


    Red wine attenuates ischemia and/or reperfusion injury; thus, it produces cardioprotection. Components of red wine, such as alcohol and polyphenolic compounds (such as resveratrol and proanthocyanidin), serve equally for its cardioprotective property but through two different mechanisms. Polyphenolic antioxidants scavenge the free radicals while alcohol protects from cellular injury by adapting the heart to oxidative stress. The overall effect of these two components of red wine makes red wine a potent therapeutic agent for the amelioration of myocardial injury associated with ischemia-reperfusion.


    The research work reported in this article was supported by a grant from the Canadian Institutes of Health Research. Dr Dev D Santani was a visiting professor from the Department of Pharmacology, L M College of Pharmacy, Ahmedabad, India.

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    Significance of Wine and Resveratrol in Cardiovascular Disease: French Paradox Revisited

    Ramesh Vidavalur, MD,1 Hajime Otani, MD,2 Pawan K Singal, PhD,3 and Nilanjana Maulik, PhD4

    1 Department of Pediatrics, University of Connecticut Health Center, Farmington, Connecticut, USA

    2 Kansai Medical University, Moriguchi, Japan

    3 Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba

    4 Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA

    Correspondence: Dr Nilanjana Maulik, Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-1110, USA. Telephone 860-679-2857, fax 860-679-2825, e-mail


    Many recent studies have reported promising health benefits from red wine consumption. The present article reviews some of the key studies, and the known mechanisms for these beneficial effects. Evidence from different experimental studies, including from the authors’ laboratories, have suggested that these beneficial effects are due to polyphenols found in red wine, especially resveratrol in grape skins. These benefits include a reduction in cardiovascular morbidity and mortality, lung cancer and prostate cancer by approximately 30% to 50%, 57% and 50%, respectively. Polyphenols possess antioxidant, superoxide-scavenging, ischemic-preconditioning and angiogenic properties. Some of these properties of polyphenols may explain their protective effects on the cardiovascular system, as well as other body organs. In fact, results from several epidemiological, case-control and prospective studies have prompted the United States Department of Health and Human Services to recommend moderate alcohol consumption in its national health promotion and disease prevention initiative, Healthy People 2010. Further studies are warranted to describe the precise molecular mechanisms for these potential beneficial effects of red wine on the general health of the population, particularly on cardiovascular morbidity and mortality.

    “God in his goodness sent the grapes, to cheer both great and small; little fools drink too much, and great fools not at all.”
    – Anonymous

    Since ancient times, in various cultures and religions, there has been a strong belief that alcohol offers important health benefits. In recent years, the idea that regular alcohol consumption protects against cardiovascular disease has gained momentum. A large number of studies have shown a ‘U-’ or ‘J-shaped’ relationship between alcohol intake and mortality from all causes (1–3). Individuals who drink moderately reduce their risk of dying from heart disease by approximately 40% (4). However, it is not clear whether the apparent protective effects of moderate alcohol intake are the same for all subsets of the population and for all types of alcoholic beverages. In light of the well-publicized ‘French paradox’ (5), researchers have focused on studying the mechanisms of the protective effects of moderate alcohol consumption, particularly on the cardiovascular system (6,7). A moderate amount of alcohol, according to ‘Anstie’s rule’, seems to be less than three standard drinks daily. American Dietary Guidelines (8) define moderation as having no more than one drink per day for women and no more than two drinks per day for men. The difference in limits between sexes seems to be based on the differences due to both weight and metabolism. In this regard, we also need to give consideration to age and other individual risk factors. A recent meta-analysis of eight studies on wine and beer consumption and cardiovascular risk showed that wine-drinking individuals have a relative risk of 0.68 compared with nondrinkers (9). The present article systematically reviews the role of wine drinking in reducing cardiovascular risk, and also reviews mechanisms of cardiovascular protection.

    Epidemiological Evidence

    It has long been known that high dietary fat intake is associated with excessive mortality from cardiovascular risk factors. Data examining 40 dietary variables from 40 countries at various levels of economic development showed a significant positive correlation between mortality from coronary artery disease and a lipid score combining the intake levels of cholesterol and saturated fat (cholesterol-saturated fat index) (10). However, the French paradox, as described by St Leger et al (6), states that there is a strong inverse correlation between wine intake and coronary mortality, which is independent of fat intake or other dietary constituents. In countries such as France and Finland, some researchers have attributed this protective effect to an increased consumption of plant foods, as well as regular, moderate consumption of wine. There are many variables that affect the precise validity of these data because the conclusions may be affected by confounding factors (eg, lifestyle and socioeconomic status) that are difficult to control. On the other hand, case-control studies have been published that used matched controls to examine the association between alcohol and end points such as myocardial infarction (MI), atherosclerosis and sudden cardiac death (11,12). The Copenhagen Heart Study (13), a prospective follow-up of 13,000 individuals, showed an inverse correlation between the amount of alcohol consumed and coronary risk, but only for wine drinkers, and not for consumers of beer and spirits.

    Although these studies have generally concluded that light to moderate alcohol intake significantly reduces cardiac mortality, participants may not have been representative of the general population, given the population’s variability in lifestyle, and in the frequency and pattern of drinking. The prospective cohort studies have also shown that the relative risk of coronary death is reduced by 30% with moderate alcohol consumption, which is consistent between sexes, and across different races and high-risk groups such as those with insulin-dependent diabetes mellitus (14). Although it is impossible to confirm these data by conducting a multicentre randomized controlled study due to logistical and ethical reasons, the above studies provide compelling evidence that light to moderate consumption of alcohol is associated with reduced morbidity and mortality from cardiovascular diseases.

    Biological Comounds in Wine

    Wines contain important substances that affect their taste, bitterness, colour, preservation and oxidation when exposed to air. Wine phenolic compounds include flavonoids and nonflavonoids. Flavonoids are polyphenols consisting of anthocyanins. Nonflavonoids include hydroxycinnamic acid, benzoic acid, tannins and stilbenes. Both flavonol and nonflavonols have been implicated in the so-called French paradox. Recently, there has been an increased focus on stilbene and resveratrol with respect to their cardioprotective effects, which are discussed later on. Procyanidin, another phenolic compound, has also been shown to possess endothelium-dependent relaxing activity in blood vessels in vitro (15).

    The specific effects of these polyphenolic compounds found in red wine have been shown to decrease the risk of coronary artery disease by attenuating the oxidation of low density lipoprotein (LDL) (16). Oxidized LDL has been suggested to play a major role in the pathogenesis of atherosclerosis (17), and is also responsible for decreasing anti-inflammatory activity and improving impaired endothelial function. Phenolic antioxidants found in red wine inhibit the upregulation of nuclear factor-kappa B (NF-κB), which is a redox-sensitive nuclear transcription factor with a key role in immune and inflammatory responses in isolated monocytes (18). Resveratrol, a polyphenol, is discussed in detail later on.

    Cardiovascular Effects of Wine and Other Alcoholic Beverages

    Effect on Serum Lipids

    Wine drinkers have higher high density lipoprotein (HDL) levels than that of nonwine drinkers (19). High HDL levels are known to exert a protective effect against coronary vascular events due to atherosclerosis. Rimm et al (20) have shown that for every gram of alcohol consumed per day, the HDL level increases by 0.004 mmol/L. Regular alcohol consumption may be associated with an increase in the synthesis of lipoproteins, a reduction in the degradation of HDL-cholesterol and a higher hepatic metabolism of LDL-cholesterol (21). The ingestion of red wine is associated with an increase in the antioxidant activity in the serum, an increase in apolipoprotein A-1 and a decrease in the atherogenic agent lipoprotein(a), mainly due to the presence of flavonoids and stilbenes (22). It has been further suggested that this increase in antioxidant activity in patients regularly drinking red wine may be the primary factor inhibiting LDL oxidation, which, in turn, reduces atherosclerotic complications.


    The effects of red wine on homeostasis and platelet function have been extensively studied. Platelet aggregation is a fundamental phenomenon in the genesis of atherosclerotic plaques in coronary vessels. Several studies have documented that moderate wine consumption reduces platelet aggregation, thereby producing an antiatherosclerotic effect in the arteries. Polyphenols in wine may exert their effects by reducing prostanoid synthesis from arachidonate. In addition, it has been suggested that polyphenols may reduce platelet activity mediated by nitric oxide (NO) (16). Moreover, polyphenols increase vitamin E levels while decreasing the oxidation of platelets exposed to oxidative stress. It has also been shown that wine drinkers have reduced fibrinogen levels and increased fibrinolytic activity, probably due to upregulation of tissue plasminogen activator in preformed plaques (17,20). Resveratrol and quercetin seem to play an important role in this antiplatelet aggregating effect, as discussed later on.

    Role of NO

    NO, produced by endothelial nitric oxide synthase (eNOS), is the key regulator of vascular homeostasis, including vascular tone and blood pressure. Decreased eNOS protein and reduced NO production is an early and persistent feature of vascular dysfunction in diabetes, hypertension and heart failure (18). It can also lead to vasoconstriction, platelet aggregation, smooth muscle cell proliferation and leukocyte adhesion. The red wine polyphenols have been shown to trigger NO-dependent signalling, which mediates a number of cardioprotective actions of NO, including a decrease in contractility, coronary resistance, myocardial oxygen demand and improvement of metabolic function (19). The increased bioavailability of NO plays an important role in polyphenol-dependent cardioprotective mechanisms through the regulation of antioxidant and NO-producing enzymes.

    Biological compounds in wine as antioxidants

    According to one hypothesis of atherosclerosis, LDL oxidation plays a major role in the early development and progression of atherogenesis (17). Oxidized LDL is more atherogenic than native LDL, because it contributes to the cellular accumulation of cholesterol and oxidized lipids, and to foam cell formation. Many studies have demonstrated the antioxidative properties of red wine (eg, against in vitro LDL oxidation), which are attributed mainly to the presence of phenolic compounds (21). This effect seems to be dependent on the concentration of polyphenols in the wine products. In vivo studies have also shown that the daily consumption of 400 mL of red wine for two weeks increases plasma and LDL-associated polyphenols, and protects LDL against copper ion-induced oxidation (22). Quercetin and catechin, which are present in red wine, have been shown to possess free radical-scavenging properties (23). Increased production of reactive oxygen species within a vessel is considered to be an important mechanism for endothelial dysfunction. Specifically, superoxide reacts rapidly with NO to form peroxynitrite, which is both an intracellular and extracellular metabolite, causing loss of NO bioavailability by oxidizing tetrahydrobiopterin, which is a crucial cofactor for NOS. Wine polyphenols have been shown to scavenge peroxynitrite, and exhibit antioxidant, anti-inflammatory and antiatherogenic effects (22).

    Anti-inflammatory effects

    Inflammation plays a significant role in the initiation and progression of atherosclerosis, which may predispose an individual to major cardiovascular adverse events. Recent studies have examined the anti-inflammatory effects of wines, with a particular focus on some of the polyphenolic compounds found in white wine, namely, tyrosol and caffeic acid. Bertelli et al (24,25) showed an inhibitory effect of tyrosol and caffeic acid on lipopolysaccharide-induced tumour necrosis factor-alpha, interleukin (IL)-1β and IL-6 production from the peripheral blood mononuclear cells of healthy volunteers.

    Regular, moderate consumption of red wine increases the plasma concentration of IL-6, which has anti-inflammatory activity that may limit the production of the proinflammatory cytokines IL-1 and tumour necrosis factor-alpha (26). In their open, prospective, randomized, crossover, single-blind trial, Estruch et al (27) showed that the consumption of 30 g of ethanol once daily (as red wine) significantly reduced mean plasma fibrinogen, high-sensitivity C-reactive protein and IL-1. They also found that circulating endothelial cell adhesion molecules, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which may be early markers of atherosclerosis, were significantly reduced (27).

    Cellular effects

    Polyphenols, present in wine, exhibit many important cellular effects, which may contribute to beneficial effects on health (Figures 1 and 2). In a recent study by Blanco-Colio et al (18), NF-κB production in peripheral mononuclear cells was significantly decreased by red wine consumption in human volunteers. In cultured smooth muscle cells, the inhibition of platelet-derived growth factor receptor by catechins in red wine flavonoids was observed.

    Figure 1
    Molecular mechanisms of cardioprotection by wine extracts. Cox Cyclooxygenase; eNOS Endothelial nitric oxide synthase; ICAM Intercellular adhesion molecules; iNOS Inducible nitric oxide synthase; NO Nitric oxide; VCAM Vascular cell adhesion molecules.

    Figure 2
    Mechanisms of resveratrol-induced anti-inflammatory activity in cardioprotection.

    Because all these effects play an important role in the initiation, progression and organization of atherosclerotic plaques, their blockade may represent an additional mechanism of vascular protection by red wine polyphenols. It is likely that cardioprotection by red wine is mediated by its polyphenolic components, resveratrol and proanthocyanidin. Studies from our laboratory have shown that the red wine extracts proanthocyanidin and resveratrol are not only potent scavengers of peroxyl radicals, but they also reduce the extent of lipid peroxidation in the ischemic-reperfused myocardium. Wine, as opposed to other sources of polyphenols and antioxidants, is unique in that it is the richest source of natural polyphenol antioxidants, especially resveratrol.

    Preconditioning effects

    In addition to reducing vascular risk factors for ischemic heart disease, wines can directly protect the heart from ischemia-reperfusion injury by a preconditioning effect. The preconditioning phenomenon of the heart was originally reported by Murry et al (28), who showed that cyclic episodes of a brief period of ischemia and reperfusion rendered the heart tolerant to subsequent longer exposures to ischemia-reperfusion injury. Ischemic preconditioning cannot be used in humans for ethical reasons; therefore, pharmacological preconditioning has emerged as an ideal alternative to ischemic preconditioning. Thus far, many pharmacological agents have been found to produce similar preconditioning effects, and these effects are critically mediated by NO (29). Polyphenols, especially resveratrol, found in grapes play a significant role in this preconditioning effect, thus highlighting a potential therapeutic role for red wine. Various molecular mechanisms behind this pharmacological preconditioning have been elucidated by our laboratory, and are described in Figure 3.

    Figure 3
    Molecular pathways and effects of resveratrol-induced cardioprotection in rodent models from the authors’ laboratory. Bcl2 B-cell lymphoma protein 2; eNOS Endothelial nitric oxide synthase; ERK1/2 Extracellular signal-regulated kinase 1/2; HO-1 Heme oxygenase-1; iNOS Inducible nitric oxide synthase; MAPK Mitogen-activated protein kinase; NF-kappaB Nuclear factor-kappa B; Trx Thioredoxin; VEGF Vascular endothelial growth factor.


    Myocardial angiogenesis
    Therapeutic angiogenesis has emerged as a promising strategy for the treatment of patients with ischemic limb and heart disease. Therapeutic angiogenesis improves blood flow to ischemic tissue through the induction of neovascularization by angiogenic agents administered either as a recombinant protein or by gene therapy. In the past 10 years, alternative revascularization and angiogenesis strategies have progressed from bench to bedside, focusing on capillary sprouting and/or growth of new vessels to replace the old ones. However, most of the strategies involve the delivery of growth factors. Thus far, very little success with these strategies has been demonstrated for various reasons.

    In this regard, our data show increased capillary density in the resveratrol-pretreated infarcted heart, along with increased concentrations of the proangiogenic protein vascular endothelial growth factor (VEGF) and its receptor Flk-1. Most notably, we found increased DNA-binding activity of NF-κB and specificity protein 1 in the myocardium pretreated with resveratrol. In a previous study, Sasaki et al (30) documented hypoxia/reoxygenation-mediated myocardial angiogenesis via an NF-κB-dependent mechanism in a chronic MI rat model. In this study, inhibition of angiogenesis by the administration of pyrrolidine dithiocarbamate, an NF-κB inhibitor, was successful in demonstrating the essential role of NF-κB in myocardial angiogenesis. Therefore, NF-κB activation by resveratrol may be of critical importance for the initiation of an angiogenic response in the rat MI model. Thus, resveratrol appears to differentially regulate NF-κB activity depending on the types of tissues and cells. The direct free radical-scavenging action of resveratrol inhibits LDL oxidation in the vascular wall and upregulation of NF-κB in inflammatory cells, leading to inhibition of atherosclerosis; moreover, the resveratrol-induced enhanced DNA-binding activity of NF-κB improves coronary circulation by increasing the generation of NO, and promotes angiogenesis by increasing the generation of angiogenic cytokines in the ischemic heart. Of note, the induction of eNOS and inducible NOS (iNOS) by resveratrol in the myocardium provides evidence supporting the hypothesis that resveratrol regulates endothelial cell growth; this is also supported by the presence of increased perfused capillaries. eNOS is constitutively expressed and can be stimulated by interventions; on the other hand, iNOS is a cytokine-induced isoenzyme (31). The eNOS isoform has been reported to play an important role in circulatory function during heart failure, whereas the iNOS isoform may have an important role in hemodynamics early after MI (32). iNOS modulates arterial hemodynamics in large conduit arteries, whereas eNOS regulates resistance of the peripheral vessels (33).

    Numerous experimental studies have shown that very low concentrations of NO, produced from eNOS, or pharmacological concentrations of exogenous NO, produced by NO donors, reduce apoptotic cell death (34,35). Previously, we found that besides eNOS induction, iNOS was also significantly induced in all resveratrol-treated groups. Recent studies have shown that eNOS-generated NO plays an important role in many VEGF-induced actions. VEGF has been shown to induce the production of NO in rabbit, pig, bovine and human vascular endothelial cells (36). The inhibition of NO production by eNOS inhibitors significantly reduces VEGF-induced mitogenic and angiogenic effects (37). eNOS-generated NO has been implicated as one of the important mediators for VEGF-induced hemodynamic changes and microvascular permeability.

    Although eNOS was originally described as a constitutive enzyme, recent studies indicate that a variety of stimuli, including hypoxia, shear stress, inflammatory cytokines, high glucose levels and injury, can modulate eNOS expression and activity (38,39). In vitro experiments have shown that the activation of Flk-1/kinase insert domain receptor (KDR) induces proliferation and migration of endothelial cells, as well as expression of eNOS and iNOS (40,41). NO is a pleiotropic molecule that affects a wide variety of biochemical and physiological functions, including the regulation of vascular tone and vascular remodelling (42). A potential therapeutic target for NO is angiogenesis (43). Incubation of human vascular smooth muscle cells with NO donors enhances VEGF synthesis, and inhibition of NOS abrogates VEGF production (44).

    Inhibitors of eNOS have been shown to block VEGF-induced endothelial cell migration, proliferation and tube formation in vitro, as well as VEGF-induced angiogenesis in vivo. In the absence of eNOS inhibition, VEGF stimulates phosphatidylinositol-3 kinase and Akt-dependent phosphorylation of eNOS, resulting in the activation of eNOS and increased NO production. The Flk-1/KDR receptor of VEGF is predominantly involved in eNOS phosphorylation. Although both the tyrosine kinase receptors VEGF receptor-1 (Flt-1) and VEGF receptor-2 (Flk-1/KDR) are necessary for VEGF signalling, there is a basic difference between the two receptors (45). While stimulation of Flt-1 is linked to cell migration, Flk-1/KDR activation is associated with both cell migration and proliferation, which, of note, occurs by the mitogen-activated protein kinase cascade (46). Interestingly, while the induction of VEGF and Flt-1 expression occurs within a very short time, the induction of KDR expression does not occur until days later (47). Flk-1/KDR is believed to be involved in eNOS expression, because a Flk-1/KDR-selective mutant, and not a Flt-1 receptor-selective mutant, can increase eNOS expression.

    In a recent study, Das et al (48) showed that resveratrol induces the expression of iNOS, eNOS, VEGF and Flk-1/KDR in a coordinated fashion in the order listed. Immunohistochemistry detected increased expression of iNOS, eNOS, VEGF and Flk-1/KDR in the hearts of resveratrol-fed rats subjected to 30 min of ischemia and 2 h of reperfusion compared with hearts of nonresveratrol-fed rats. A growing body of evidence indicates that resveratrol can pharmacologically precondition a heart in an NO-dependent manner (49). A number of other studies have also shown a direct role of NO in resveratrol-mediated cardioprotection (15,50–59). Several studies have reported that resveratrol can induce eNOS and iNOS expression. For example, resveratrol induced the expression of eNOS in human umbilical vein endothelial cells (60). In addition to its long-term effects on eNOS expression, resveratrol also enhances the production of bioactive NO in the short term (within 2 min), suggesting a role for iNOS. Our results support these previous observations, because we also observed iNOS expression within 24 h, whereas eNOS expression did not become apparent until after three days. In another study, resveratrol induced the expression of iNOS in cultured bovine pulmonary artery endothelial cells (61).

    Neovascularization in the infarcted rat myocardium
    A modern experimental strategy for treating myocardial ischemia is to induce neovascularization of the heart through the use of ‘angiogens’ (ie, by angiogenesis). Recent studies have shown that coronary collateral vessels protect the ischemic myocardium after coronary obstruction. Various interventions are being tested with the aim to improve arterial blood supply through the formation of coronary collateral vessels (angiogenesis) to the ischemic myocardium. Factors such as fibroblast growth factor and VEGF, which stimulate collateral growth, are expected to exert a protective effect against MI. Indeed, VEGF is a major regulator of angiogenesis and vasculogenesis (62). A strong temporal and spatial correlation exists between VEGF expression and angiogenesis in both animals and humans (63,64). The biological functions of VEGF, triggered by external stimuli, are initiated through the activation of intracellular signal transduction cascades involving specific kinases (65). In this respect, VEGF behaves as a classic stress-induced gene.

    Conventional therapeutic approaches to restore flow to a localized segment are thrombolysis, angioplasty and bypass surgery. Tissue hypoxia/ischemia, as well as pharmacological agents such as resveratrol (polyphenol), have been identified as being very important for the induction of new vessel growth. Progressive, chronic coronary artery occlusion has been shown to induce the development of collateral arteries, re-establishing and maintaining blood flow to the at-risk myocardium via the growth of new capillary vessels (angiogenesis). Studies from our laboratory, as well as from others, have already confirmed the protective role of collaterals against myocardial ischemia and cell death (66–69). In adult rat myocardium (left ventricular), we have successfully shown that resveratrol significantly upregulates the protein expression profiles of VEGF and its tyrosine kinase receptors (Flk-1/KDR and Flt-1), as well as other angiogenic factors such as angiopoietin 1 and 2 and their receptor Tie-2 (70). We were also able to show increased capillary/arteriolar density, and improved left ventricular function and blood flow by resveratrol preconditioning in a rat model of chronic MI (71).

    We have recently demonstrated resveratrol-mediated induction of thioredoxin-1 (Trx-1) in the heart; Trx-1 is an intracellular redox regulator that is important in the regulation of transcription factors (72–74). Trx is generally located in the cytosol but translocates into the nucleus in response to various stimuli, such as oxidative stress. Several stress studies have reported the induction and translocation of Trx along with heme oxygenase-1 (HO-1). Recent reports suggest that the Trx system contributes to the upregulation of HO-1 protein levels, as well as HO-1 promoter activity, under conditions associated with inflammation and increased oxidative stress (75,76). Turoczi et al (77) found that transgenic mouse heart overexpressing Trx-1 are resistant to ischemia-reperfusion injury, as evidenced by improved postischemic ventricular function recovery and reduced myocardial infarct size compared with the corresponding wild-type mouse hearts. HO-1 is a cytoprotective enzyme that plays an important role in host defense against oxidative stress (78). Recently, Juan et al (79) reported that resveratrol-mediated HO-1 induction is modulated at both the transcription and translation levels in human aortic smooth muscle cells in vitro. We have previously shown a sequential activation of Trx and HO-1, as well as the proangiogenic factor and cardioprotective molecule VEGF in human coronary artery endothelial cells, and in rat neonatal cardiomyocytes and rat aortic smooth muscle cells in vitro. We have also shown that adjunctive treatment with tin-protoporphyrin significantly inhibits resveratrol-induced angiogenic activities in vitro and in vivo, as indicated by decreased tubulogenesis and capillary density. This in agreement with an earlier report showing that the overexpression of HO-1 augments the angiogenic effect of endothelial cells (80), and that the activation and overexpression of HO-1 leads to the upregulation of VEGF synthesis.

    Resveratrol-mediated expression of Trx-1, HO-1 and VEGF has been found to reduce infarct size in a rat MI in vivo model. The cardioprotective effect is significantly attenuated by tin-protoporphyrin, which may be explained by a decrease in VEGF expression. It has been reported previously that the redox protein Trx-1 increases hypoxia inducible factor-1-alpha protein expression under both normoxic and hypoxic conditions. This is found to be associated with augmented VEGF formation and increased tumour angiogenesis in vivo (81). The hypoxia inducible factor-1 complex influences the expression of many genes, including VEGF (82). Thus, VEGF is implicated as a major angiogenic factor leading to the development of new vessels from pre-existing capillaries (83,84). Transfection of cells with human Trx-1 has been found to increase the overall production of VEGF in MCF-7 breast cancer, HT-29 colon cancer and WEHI7.2 lymphoma cells (85). The beneficial effects of resveratrol may have a multifactoral basis, because resveratrol is also found to augment NO production in endothelial cells (86), and in the kidney (58) and heart (87). Giovannini et al (58) and Naderali et al (88) have indicated that the upregulation of NO is a principal factor in the anti-ischemic function of resveratrol. We have also shown that the anti-ischemic effects of resveratrol are blocked by NG-nitro-L-arginine methyl ester, an inhibitor of NO synthesis, thus indicating that NO is a mediator of resveratrol preconditioning of the heart (87). Another study has indicated a strong reciprocal relationship between VEGF and NO in a rat model of chronic NO blockade (89). It is well accepted that VEGF-induced neovascularization strongly depends on the generation of NO, because NO inhibitors are found to reduce the angiogenic potential of endothelial cells (90). Therefore, resveratrol-mediated pharmacological preconditioning for cardioprotection is a complicated molecular mechanism. A simplified diagram explaining the above mechanisms is depicted in Figure 1. Future studies are warranted to determine whether regular wine drinking promotes long-lasting cadioprotection through activation of iNOS and downstream cardioprotective signalling.

    A phytoestrogen effect

    Based on its structural similarities to diethylstilbestrol, resveratrol is recognized to be a phytoestrogen. Resveratrol can bind to the estrogen receptors (ERs), thereby activating transcription of estrogen-responsive reporter genes in transfected cells (91,92). Resveratrol has been shown to function as a super-agonist when combined with estradiol (E2), and can induce the expression of estrogen-regulated genes (93); however, several other studies show conflicting results. In another study using the same cell line, resveratrol showed antiestrogen activity; specifically, it suppressed progesterone receptor expression induced by E2. Both isomers of resveratrol have been shown to possess very good estrogenic activity at only moderate concentrations (greater than 10 μM), whereas at lower concentrations (less than 1 μM), antiestrogenic effects prevail (94). Most in vivo studies have failed to confirm the estrogenic potential of resveratrol. At physiological concentrations, resveratrol did not induce any changes in uterine weight, uterine epithelial cell height or serum cholesterol (95). Only at a very high concentration did resveratrol modulate the serum cholesterol-lowering activity of E2 (96). Resveratrol given orally, as well as subcutaneously, did not affect uterine weight at any concentration ranging from lowest to highest (0.03 mg/kg/day to 120 mg/kg/day) (97), whereas in another related study, resveratrol reduced uterine weight and decreased the expression of ER-α mRNA and protein, as well as progesterone receptor mRNA (98). In contrast, resveratrol was found to possess estrogenic properties in stroke-prone spontaneously hypertensive rats (99). Ovariectomized rats fed resveratrol at a concentration of 5 mg/kg/day showed an attenuation of increases in systolic blood pressure. In concert with this, resveratrol enhanced endothelin-dependent vascular relaxation in response to acetylcholine, and prevented ovariectomy-induced decreases in femoral bone strength in a manner similar to E2. Recently, resveratrol was found to act as an ER agonist in breast cancer cells stably transfected with ER-α (100). In a recent study, we showed a significant induction of ER-α two, four, seven and 21 days after MI in the myocardium of resveratrol-fed rats. On the other hand, there was a decrease in ER-α two, four, seven and 21 days after MI in the myocardium of resveratrol-fed rats compared with controls (unpublished data).

    Resveratrol and other diseases

    In addition to its antiplatelet, antioxidant and estrogenic properties, resveratrol has other biochemical and physiological functions.

    Chronic inflammation and infection
    Inflammation has been implicated in many chronic ailments in humans. Resveratrol has shown promise in inhibiting the cyclooxygenase pathway, which is crucial in the production of proinflammatory molecules involved in pathogenesis of diseases such as Crohn’s disease, arthritis and psoriasis (101). Moreover, recent antiviral research in mice showed significant protection against herpes simplex infections (102). This multitude of clinical effects seems to be modulated through more complex mechanisms than simple anti-inflammatory effects. More experiments are needed to elucidate these interesting pathways of specific immune responses, which may offer attractive alternatives to current therapeutic options in the management of diseases of chronic inflammation. A recent study showed the inhibition of the growth of CagA-positive strains of Helicobacter pylori in vitro when treated with resveratrol (103). In another study, resveratrol inhibited the growth of 15 clinical strains of H pylori in vitro, suggesting that the anti-H pylori activity of resveratrol may play a role in its chemopreventive effects (104).

    Anticancer effects
    While resveratrol protects the brain, kidney and heart cells, it preferentially kills cancer cells. This is due to the ability of resveratrol to suppress angiogenesis and tumour growth by decreasing VEGF expression and increasing apoptotic cancer cell death. For example, intraperitoneal administration of resveratrol causes an increase in the G2/M phase of the cell cycle, as well as apoptosis and reduced tumour growth (105). In oral squamous carcinoma cells, resveratrol causes growth inhibition, both alone and in combination with quercetin (106). In a recent study, resveratrol inhibited the growth of highly metastatic B16-BL6 melanoma cells (107). In a rat colon carcinogenesis model, resveratrol induced proapoptotic Bcl2-associated X protein expression in colon aberrant cryptic foci (108). In fact, resveratrol was found to affect three major stages of carcinogenesis and inhibit the formation of preneoplastic lesions in a mouse mammary organ culture model (109).

    Antiaging effect
    Aging is one of the prime focuses of research in both the commercial and scientific communities. Sirtuins (SIRT), a family of NAD-dependent deacetylases, especially SIRT1 to SIRT7, have been postulated to promote stress resistance and survival in times of adversity and adaptability (110). Resveratrol has also been found to increase the activity of the antiaging gene SIRT1 by 13-fold (51). Resveratrol-mediated activation of life-extending genes in human cells may open a totally new horizon for resveratrol research. Preliminary studies with resveratrol have shown promising protective effects of SIRT1 overexpression in vitro, and lifespan extension with intact learning and motor function with age in fish experiments (111,112). The proposed antiaging properties of resveratrol open up exciting possibilities for new discoveries in aging research. However, the application and translation of these data from lower organisms to human studies remain to be seen.

    Protection against stroke
    Several animal studies have raised the possibility that resveratrol may be useful in protecting against and limiting brain damage following ischemia. Rats treated with resveratrol showed decreased infarct size and motor impairment, and decreased delayed neuronal death. These important findings, observed even at lower doses, offer considerable hope for the therapeutic potential of resveratrol. Recent studies have established that after a stroke, levels of intracellular heme increase. The source of free heme is mainly from several heme-containing enzymes. Heme is a prooxidant and its rapid degradation by HO is believed to be protective against neuronal damage. Studies from our laboratory and others have shown that resveratrol, apart from direct free radical-scavenging activity, also increases HO activity, thus offering neuroprotective actions in ischemic injury of the brain (113).


    From several in vivo, in vitro and human studies, it is evident that resveratrol can protect against a variety of diseases such as ischemic heart disease, cancer, Alzheimer disease, diabetes, inflammation and infection. Even though we do not know the maximum tolerated dose of resveratrol, rodent studies have shown that treatment with up to 300 mg/kg body weight has no side effects, with variable bioavailability in different organs. New studies should be aimed at improving the bioavailability of resveratrol and discovering new analogues to help in finding more potent yet protective compounds in preventing disease. It would be interesting to identify the mechanisms behind these fascinating beneficial effects of resveratrol and other compounds in red wine, and this could herald a new chapter in alternative medicine.


    This study was supported by National Institutes of Health grants R01 HL 56803, HL R01 69910 and HL R01 HL085804 to NM.

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