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Anti-atherogenic effects of resveratrol

Abstract

Resveratrol (RS), a polyphenol compound found in grapes and grape products, including wine, peanuts and berries, exists in cis- and trans-isomeric forms. RS is believed to decrease circulating low-density lipoprotein cholesterol levels and reduce cardiovascular disease (CVD) risk. However, it is possible that RS has other mechanisms to reduce the risk of CVD without altering lipid levels. The objective of this review is to critically examine results from recent research concerning potential effects of RS on CVD. RS exerts several health benefits including anti-atherogenic, anti-inflammatory and anti-cancer effects. RS may also prevent lipid oxidation, platelet aggregation, arterial vasodilation and modulates the levels of lipids and lipoproteins. As a potent, anti-oxidant RS reduces oxidative stress and regenerates α-tocopherol, which further strengthens the anti-oxidant defense mechanism. RS has been considered safe as no significant toxic effects have been identified, even when consumed at higher concentrations. This evidence identified RS as an effective anti-atherogenic agent, which could be used in the prevention and treatment of CVD.

Introduction

Resveratrol (RS) naturally occurs as a polyphenol found in grapes and grape products, including wine, as well as other sources including nuts (Cavallaro et al., 2003). RS is also found in the root of Polygonum cuspidatum (Polygonaceae) (Jang and Pezzuto, 1999). In grapes, RS is present in the skin as both free RS and piceid (3-O-mono-D-glucoside of RS; Figure 1). RS has been demonstrated to exert a variety of health benefits including anti-atherogenic, anti-inflammatory and anti-cancer effects (Das and Maulik, 2006; Sun et al., 2008; Udenigwe et al., 2008). RS has also been shown to offer protection against ischemic injuries (Wang et al., 2002a) and neurodegenerative diseases (Fremont, 2000; Hung et al., 2000; Sun et al., 2002). A number of studies exist regarding the beneficial effects of RS on cardiovascular disease (CVD) with the positive effects being attributed to its anti-oxidant (Fauconneau et al., 1997; Martinez and Moreno, 2000; Sato et al., 2000) and anti-coagulative properties (Bertelli et al., 1996b; Soleas et al., 1997). Various anti-atherogenic mechanisms have been proposed for RS in reducing the CVD risk including alteration in lipid metabolism.

Figure 1
figure1

Structures of trans and cis isomers of resveratrol and piceid.

The objective of this review is to critically examine the results from recent research concerning potential effects of RS on CVD. This review considers the evidence supporting the effects of RS on atherosclerosis and in reducing CVD risk by various mechanisms including modulation of lipid metabolism, free radical scavenging and anti-oxidant effects, anti-inflammatory effects and platelet aggregation.

Structure and metabolism of RS

RS, a non-flavonoid polyphenolic compound, exists in cis- and trans-isomeric forms (3,4′,5-trihydroxy-stilbene, MW=228.2) and of piceid (Figure 1). Bioavailability and metabolism of RS have previously been reviewed in detail (Udenigwe et al., 2008). RS gets rapidly metabolized in liver and intestine by glucuronidation and sulphonation (Bertelli et al., 1996a). Over 90% of metabolized RS might be present in plasma of rats (Meng et al., 2004). In a pharmacokinetic study of RS in mice, rats and human, it was shown that within 24 h after administration of RS at a dose of 0.03 mg/kg body weight, nearly 50% of RS gets excreted through urine. However, as <25% of the RS was found in the urine with the dose of 1 mg/kg, these results suggest the rapid gastrointestinal absorption of RS in all the three species studied (Meng et al., 2004). In another study, the half life of RS in plasma was reported to be 12–15 min after oral administration in rats (Gescher and Steward, 2003).

Effect of RS on lipids and lipoprotein levels

It is well known that hypercholesterolemia and other lipid abnormalities are important indicators and risk factors for CVD. High low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) levels form the major risk markers that are directly and positively correlated with CVD risk. Penumathsa et al. (2007) have examined the effect of RS administration at 20 mg/kg body weight for 14 days on high cholesterol diet-induced hypercholesterolemia in rats. Results showed that treatment with RS reduced not only lipid levels including LDL cholesterol, and triglycerides but also the myocardial complications by influencing infarct size, apoptosis and angiogenesis. Recently Rocha et al. (2009) have shown a significant reduction in total and LDL cholesterol levels in high fat diet-fed rats after treatment with RS in drinking water at 1 mg/kg body weight. Other studies have shown effects of RS in reducing total, LDL and VLDL cholesterol levels in vivo (Miura et al., 2003). Treatment of RS at 0.025% diet for 8 weeks to hamsters fed with high fat diets improved lipid profiles by reducing levels of total cholesterol and triglycerides, apolipoprotein-B, lipoprotein-a and cholesterol ester transport protein (Cho et al., 2008). RS also reduced endogenous cholesterol synthesis by downregulating hepatic HMG-CoA reductase mRNA expression, the rate-limiting enzyme in sterol biosynthesis (Cho et al., 2008). Ahn et al. (2008) studied effects of supplementation of RS at 0.0125% provided in diet on lipid metabolism and related gene expression. Results showed that RS reduced plasma levels of total and free cholesterol. Treatment with RS also decreased levels of hepatic total lipids and triglycerides, as well as their accumulation. In addition, the authors observed that RS feeding prevented steatohepatitis induced by atherogenic diets through modulation of expression of genes involved in lipogenesis and lipolysis.

Long-term effects of RS supplementation on lipid levels and atherosclerosis at 0.02 and 0.06% diet for 20 weeks in apoE-deficient mice were studied by Do et al. (2008). Results showed that RS supplementation effectively reduced total and LDL cholesterol values, while increasing HDL levels in plasma. RS was also found to reduce atherosclerotic lesions and activity of hepatic HMG-CoA reductase. Rivera et al. (2009) in a long-term study administering RS orally at 10 mg/kg for 8 weeks to obese Zucker rats have found reductions in plasma levels of triglycerides, total cholesterol and free fatty acids and hepatic total lipids.

Treatment of RS to nephritic rats at 50 mg/kg body weight per day for 14 days substantially reduced hyperlipidemia and suppressed hepatic synthesis of lipids (Nihei et al., 2001). In a study by Miura et al. (2003), hepatoma bearing rats were treated with RS at a dosage of 10 and 50 p.p.m. for 20 days. Results showed a reduction in hyperlipidemia by RS treatment by increasing fecal excretion of bile acids and sterols. But in an in vivo study, RS supplementation to rabbits with hypercholesterolemia resulted in an absence in reducing circulating cholesterol levels or atherosclerosis (Wilson et al., 1996). Since the early 1980s, RS has been reported to inhibit hepatic triglyceride synthesis and reduce hepatic cholesterol and triglyceride accumulation in rats (Arichi et al., 1982).

In vitro studies have also shown promising beneficial effects of RS on lipid metabolism (Kollar et al., 2000). RS at 5 μM concentration led to a 50% reduction in LDL secretion by human liver cells in vitro after 24 h treatment (Pal et al., 2003). However, RS caused only a modest reduction in the activity of squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis (Laden and Porter, 2001). In HepG2 human hepatocarcinoma cells, RS effectively and dose dependently reduced apolipoprotein-B production and secretion of triglycerides and cholesterol esters and hence, reducing LDL production. These results suggest that RS effectively modulates hepatic lipid metabolism (Goldberg et al., 1995). Reduction in synthesis of fatty acid and TG was observed in isolated normal rat hepatocytes treated with 25 μM concentration of RS (Gnoni and Paglialonga, 2009). This observation represents a possible mechanism for RS in reducing TG and other lipoprotein levels in circulation. Hepatic cells on in vitro treatment with RS decreased secretion of esterified cholesterol and triglycerides, which indicates the inhibition of lipoprotein metabolism in liver by RS (Gaziano, 1994; Goldberg et al., 1995).

However, various other studies have failed to show a change in lipids and lipoprotein profile after treatment with RS in vivo (Wilson et al., 1996; Soleas et al., 1997; Turrens et al., 1997, 1999; Fremont, 2000; Wang et al., 2002b). Table 1 shows a list of studies analysing the effects of RS on lipid and lipoprotein levels in various experimental conditions. The discrepancies between different studies could be the difference in various experimental models used; however, it is of concern that such a level of disparity exists among results of studies conducted to date. Although RS has been known to reduce CVD risk by altering blood lipid levels and reducing the synthesis of cholesterol, other mechanisms independent of circulating lipid levels have also been proposed (Figure 2).

Table 1 Effects of RS on lipid metabolism
Figure 2
figure2

Possible anti-atherogenic mechanisms of resveratrol. ↑ Increase, ↓ Decrease, ApoB, Apolipoprotein-B; CETP, Cholesterol ester transport protein; COX, Cyclo-oxygenase; FC, Free cholesterol; FFA, Free fatty acids; HDL, High density lipoprotein; IL, Interleukin; LDL, Low density lipoprotein; Lpn(a), Lipoprotein-A; LPG, Lipid peroxodation; PGE, Prostaglandin-E; ROS, Reactive oxygen species; RNS, Reactive nitrogen species; TC, Total cholesterol; TD, Triglyceride; TNF-α, Tumour necrosis factor alpha; VCAM, vascular cell adhesion molecule; VLDL, Very low density lipoprotein.

Cardioprotection through anti-oxidant activity of RS and its role in oxidative stress management

It has been widely accepted that natural and dietary anti-oxidants have a vital role in preventing various diseases caused by oxidative stress. Oxidative stress impacts CVD risk, including atherosclerosis, through halting the production of free radicals and the oxidation process of LDL (Kovanen and Pentikäinen, 2003). Reactive oxygen species (ROS) leads to production and accumulation of oxidized LDL at the site of atherosclerotic lesions (Yla-Herttuala, 1999). Oxidative stress also progressively leads to the development of atherosclerosis by contributing to the formation of macrophage foam cells and causing endothelial dysfunction (Mietus-Snyder et al., 2000). RS was found to significantly decrease oxidative stress markers including serum glycated albumin and urinary 8-hydroxyguanosine in stroke prone, spontaneously hypertensive rats (Mizutani et al., 2001). RS also enhances the activities of catalase and reduces ROS production in cardiac tissue of guinea pigs (Floreani et al., 2003). Rocha et al. (2009) have shown a reduction in oxidized LDL in high fat diet-fed rats treated with RS for 45 days at a dose of 1 mg/kg per day. All of the above results suggest that RS effectively inhibits the lipid peroxidation in vivo. The anti-oxidative properties of RS were suggested as the mechanism underlying its diverse effects including anti-atherogenic effects (Fremont, 2000).

Inhibitory effect of RS on ROS production and lipid peroxidation

Numerous investigations have reported that RS inhibits oxidative stress by scavenging ROS and attenuating peroxyl radicals and hydrogen peroxide (Jang and Surh, 2001; Liu et al., 2003; Shigematsu et al., 2003; Chen et al., 2004; Leiro et al., 2004). Inhibition of both intracellular and extracellular production of ROS by RS has been demonstrated with a concentration ranging from 1 to 100 μmol/l (Jang and Surh, 2001). RS has demonstrated strong anti-oxidant properties by reducing the rate of cytochrome C oxidation by hydroxyl radicals, produced by ultraviolet irradiation of hydrogen peroxide (H2O2) (Turrens et al., 1997). RS has also shown to scavenge hydroxyl radicals (Soares et al., 2003) and inhibit superoxide radical and H2O2 produced by macrophages stimulated by lipopolysaccharides (LPS) or phorbol esters. RS effectively reduces 3H-arachidonic acid release induced by LPS, phorbol esters or exposure to superoxide or H2O2 (Martinez and Moreno, 2000) and significantly lowers levels of thiol proteins in platelets isolated from humans (Olas et al., 2004). Leonard et al. (2003) have demonstrated RS to be a strong anti-oxidant by scavenging hydroxyl and superoxide radicals and protect the cells by preventing lipid peroxidation in the cell membranes as well as DNA damage. RS has been shown to prevent lipid peroxidation and inhibit uptake of oxidized LDL (Fremont et al., 1999; Leighton et al., 1999; Bhavnani et al., 2001). This inhibition of lipid peroxidation by RS could arise from RS’ strong anti-oxidant effect and its ability to inhibit ROS generation (Fremont et al., 1999; Olas and Wachowicz, 2002).

Oxidation of LDL cholesterol is strongly associated with risk of CVD (Holvoet, 2004). In rat liver microsomes, RS inhibited iron-induced as well as ultraviolet-irradiated lipid peroxidation and prevented LDL oxidation by copper (Fauconneau et al., 1997; Miura et al., 2000). RS could effectively prevent oxidative LDL modification by inhibiting lipoxygenase enzyme activity (Maccarrone et al., 1999; Kovanen and Pentikäinen, 2003). Polyphenols in red wine including RS have been reported to inhibit LDL oxidation; this effect was found to be stronger than the well-known anti-oxidant α-tocopherol (Frankel et al., 1993). RS also prevents the oxidation of polyunsaturated fatty acids found in LDL (Miller and Rice-Evans, 1995) and inhibits the oxidized LDL uptake in the vascular wall in a concentration-dependent manner (Fremont, 2000), as well as prevents damage caused to lipids through peroxidation (Frankel and Waterhouse, 1993; Leighton et al., 1999).

RS suppresses oxidative stress by increasing the synthesis of nitric oxide in ischemic re-perfused tissues (Hattori et al., 2002). RS has been shown to prevent the production of ROS stimulated by LPS (Martinez and Moreno, 2000) and to inhibit the ROS and lipid peroxidation induced by tumor necrosis factor (TNF) in a wide variety of cells including myeloid, lymphoid and epithelial cells (Manna et al., 2000). RS inhibits lipid peroxidation by effectively scavenging various free radicals including peroxyl and hydroxyl radicals in the post-ischemic re-perfused myocardium (Ray et al., 1999). Inhibition of inducible nitric oxide synthase and prevention of cytotoxic effects were also observed after treatment of RS (Tsai et al., 1999; Matsuda et al., 2000).

Bradamante et al. (2004) have explained in detail the mechanism of action of RS in inhibiting lipid peroxidation. Various mechanisms through which RS exerts anti-oxidant effects are suggested (Zini et al., 1999). First, RS may compete with coenzyme Q and decreases the oxidative chain complex III. Second, RS has been found to enhance the intracellular free radical scavenger glutathione, as RS maintains cell viability and inhibits oxidation (Savaskan et al., 2003). Third, RS may increase endogenous anti-oxidants and phase 2 enzymes in cardiomyocytes, and these increased cellular defenses provide protection against oxidative injury (Cao and Li, 2004). RS and its analogues are demonstrated as effective anti-oxidants against linoleic acid peroxidation in sodium dodecyl sulphate and cetyltrimethylammonium bromide micelles (Fang et al., 2002; Fang and Zhou, 2008). The results suggested that the anti-oxidative actions involve trapping the propagating peroxyl radicals on the surface of the micelle and regenerating α-tocopherol.

Modulation of anti-oxidant enzymes by RS

Treatment with RS has been found to reduce the oxidative stress and prevent various diseases by increasing the activities of several anti-oxidant enzymes including superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase and glutathione-S-transferase in rat aortic smooth muscle cells (Yen et al., 2003; Li et al., 2006). RS has been demonstrated to maintain levels of glutathione in oxidatively stressed human peripheral blood mononuclear cells, and to elevate glutathione levels in human lymphocytes activated by hydrogen peroxide (Losa, 2003; Olas et al., 2004). A strong dose-dependent induction of phase II drug metabolizing enzymes and anti-oxidant genes was demonstrated when rats were supplemented with 0.3, 1 and 3 g/kg body weight per day of RS for 28 days (Hebbar et al., 2005). Significant reductions in oxidative stress after treatment with RS by decreasing lipid hydroperoxide and increasing anti-oxidant enzymes including superoxide dismutase in high fat diet-fed rats have been shown by Rocha et al. (2009).

Anti-inflammatory effects of RS

The role of inflammation in the process of atherosclerosis has been increasingly well recognized over the past decade. Inflammation has a significant role at all stages of atherosclerosis including initiation, progression and plaque formation. (Libby et al., 2002; Jawien, 2008). Both in vivo and in vitro anti-inflammatory effects of RS and the underlying mechanism have been suggested (Udenigwe et al., 2008). RS inhibits the activity of cyclooxygenase-2, which is the enzyme producing PGE2, a vital component to mediate inflammation (Donnelly et al., 2004). Interleukin-6 has been implicated as an important marker in the process of inflammation and the progression of atherosclerotic plaques (Ikeda et al., 2001). Cultured murine macrophages, after treatment with RS, have been shown to reduce gene expression, synthesis and secretion of interleukin-6 (Zhong et al., 1999). The inflammatory process was found to be suppressed by RS, through mediating various inflammatory markers such as inhibition of secretion of interleukin-8 and granulocyte macrophage colony-stimulating factors (Culpitt et al., 2003; Donnelly et al., 2004), endothelial-leukocyte adhesion molecules, vascular cell adhesion molecule-1, and by inhibiting the secretion of histamine and tumor necrosis factor-α (Carluccio et al., 2003).

Inhibition of vascular endothelial growth factor-induced angiogenesis appears to occur by RS impairing the ROS-dependent pathway in human umbilical vein endothelial cells. (Lin et al., 2003). Reduction in pro-inflammatory cytokine tumor necrosis factor-α was also shown by Rivera et al. (2009) after treatment of Zucker rats with RS at a dosage of 10 mg/kg body weight for 8 weeks. Pervaiz (2003) has demonstrated the influence of RS on the effect of nuclear factor-κB, an important transcription factor that regulates various mediators or inflammation including cytokines, growth factors and adhesion molecules. RS possesses strong anti-inflammatory effect by inhibiting leukocyte adhesion in ischemia–reperfusion rat model at a dose of 0.7 mg/kg (Shigematsu et al., 2003).

Endothelial dysfunction is also reported to be an important risk factor for CVD (Rodriguez-Porcel et al., 2001). Fukuda et al. (2006) have found that RS significantly increases myocardial angiogenesis in experimental myocardial infarction-induced rats through a vascular endothelial growth factor-mediated mechanism. Saiko et al. (2008) reviewed the beneficial effects of RS on arachidonic acid metabolism, where it was found that RS inhibits the conversion of phospholipids to arachidonic acid. Furthermore, RS suppresses inflammation by inhibiting cyclooxygenase-1, -2; lipoxygenases, epoxygenases and synthesis of prostaglandins and eicosanoids (Saiko et al., 2008). Hattori et al. (2002) and Hung et al. (2000) demonstrated the inhibition of inflammation and atheromatous plaque formation by RS through altering the nitric oxide generation from vascular endothelium. RS modulates the production and secretion of inflammatory mediators and thereby suppresses the thrombogenic function of polymorphonuclear cells (Rotondo et al., 1998).

Role of RS on production of vasodilators and vasoconstrictors

Endothelial cells are known to regulate and maintain a balance between vasodilators such as nitric oxide and vasoconstrictors such as endothelin-1, as well as reduce the risk of atherosclerosis by preventing atherogenesis (Davignon and Ganz, 2004). RS has been reported to influence and maintain a balance between production of vasodilators and vasoconstrictors, respectively (Fan et al., 2008). Reduction in nitric oxide production results in vasoconstriction, platelet aggregation and oxidative stress. Furthermore, RS inhibits the enzyme cyclooxygenase-1, which is a strong vasoconstrictor and has an important role in platelet aggregation (Szewczuk et al., 2004). Increased activity of nitric oxide synthase was found in pulmonary artery endothelial cells when treated with RS, which indicates the direct association of nitric oxide in vasorelaxation (Klinge et al., 2003). RS has been shown to increase the expression of nitric oxide synthase and hence, potentially protect perfused working hearts (Hattori et al., 2002), although RS failed to show such protective effect in nitric oxide synthase knockout mice (Imamura et al., 2002). These results confirm the effect of RS in balancing vasoconstrictors and vasodilators, thereby preventing platelet aggregation and oxidative stress, which leads to reduction in CVD risk.

Suppression of platelet aggregation by RS

Platelet aggregation has an important role in mediating atherosclerosis, whereby platelets adhere to cell surfaces, releasing platelet-derived growth factor and induces atherosclerosis. Enhanced or impaired platelet aggregation results in various complications including myocardial infarction, ischemia and stroke. However, RS has been shown to inhibit the aggregation of platelets (Bertelli et al., 1996b; Bhat et al., 2001; Fan et al., 2008). Suppression of platelet aggregation by RS in rabbits supplemented with hypercholesterolemic diet and reduced atherosclerosis in genetic hypercholesterolemic mice were also demonstrated (Zini et al., 1999; Wang et al., 2002b). However, RS failed to demonstrate such effects in whole blood as the mechanism might be through inhibition of mitogen-activated protein kinases in platelets (Kirk et al., 2000). Various mechanisms of action of RS have been shown to inhibit platelet aggregation including the inhibition of platelet adhesion to type I collagen, the principal step in platelet activation. Olas et al. (2002) demonstrated that pretreatment of platelets with RS prevents LPS or thrombin stimulated platelet adhesion to collagen and fibrinogen. These findings provide more insight to the suppressive effect of RS on platelet aggregation.

Safety aspects of RS treatment

Several investigations with human and various animal models have demonstrated an absence of significant toxic effects after supplementation with RS across a wide range of dosages. No toxic effects were found in rats after oral administration of 20 mg/kg per day for 28 days (Juan et al., 2002). Doses used in these studies were 1000-fold higher than the amount consumed by humans drinking one glass of red wine per day. Furthermore, no adverse effects were seen in rats supplemented with RS at 300 mg per day for 4 weeks (Crowell et al., 2004). Boocock et al. (2007) reported no toxicity in humans administered with a single dose of RS up to 5 g. The results of these studies signal that RS could be consumed for its beneficial effects without any apparent toxicity.

Summary and conclusion

RS has been shown to have an important role in maintaining human health and preventing various diseases including atherosclerosis. The anti-atherogenic actions of RS have been shown to involve various mechanisms (Figure 2). RS appears to be beneficially modulating the lipid and lipoproteins levels, inhibiting hepatic triglyceride synthesis and reducing cholesterol and triglycerides accumulation in liver. However, contradicting results emerging from some studies fail to show a change in lipids and lipoprotein profile after treatment with RS. Such discrepancies among the results of various studies may reflect differences in the various experimental models used. Promising findings by several groups have demonstrated the potential cardioprotection of RS by reducing atherosclerotic plaque formation and preventing oxidation of LDL cholesterol. Also, persuasive data suggest that RS prevents arterial vasodilation and influences infarct size, as well as apoptosis and angiogenesis. Another principal mechanism of action of RS in cardioprotection is through reduction of oxidative stress. RS possesses strong anti-oxidant potential, reducing ROS production, as well as attenuating peroxyl radicals and hydrogen peroxide. Consumption of RS also induces various anti-oxidant genes and enzymes and phase II drug metabolizing enzymes. RS downregulates pro-inflammatory cytokines thereby suppressing inflammation through nitric oxide-dependent mechanisms. RS also regulates and maintains the balance between vasodilators and vasoconstrictors and reduces the risk of atherosclerosis by preventing atherogenesis. RS has been shown to increase the expression of nitric oxide synthase and inhibit cyclooxygenase-1 and hence, have an important role in balancing vasodilation and constriction as well as platelet aggregation. In conclusion, promising evidence depicting beneficial effects of RS supports the health claim that RS could be used in the prevention and treatment of several diseases including CVD.

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Ramprasath, V., Jones, P. Anti-atherogenic effects of resveratrol. Eur J Clin Nutr 64, 660–668 (2010). https://doi.org/10.1038/ejcn.2010.77

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Keywords

  • resveratrol
  • atherosclerosis
  • lipids
  • anti-inflammatory
  • anti-oxidant

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