Vojnosanit Pregl 2013; 70(12): 1145–1150. VOJNOSANITETSKI PREGLED Strana 1145

Correspondence to: Ljiljana Gojkovi Bukarica, Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine,P.O. Box 38, University of Belgrade, 11 129 Belgrade, Serbia. Phone: +381 11 3643 395; Fax: +381 11 3643 397.E-mail: l.g.bukarica@sezampro.rs

C U R R E N T T O P I C UDC: 615.322: 615.035:615.22DOI: 10.2298/VSP120613012G

Cardiovascular effects of resveratrolKardiovaskularni efekti rezveratrola

Ljiljana Gojkovi Bukarica*, Dragana Proti *, Vladimir Kanjuh†, HelmutHeinle‡, Radmila Novakovi *, Radisav Š epanovi §

*Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty ofMedicine, University of Belgrade, Belgrade, Serbia; †Serbian Academy of Sciences and

Arts, Belgrade, Serbia; ‡Institute of Physiology, University of Tuebingen, Germany;§Clinical Hospital Center “Dr Dragiša Mišovi ”, Belgrade, Serbia

Key words:phytotherapy; stilbenes; risk assesment; cardiovasculardiseases; diet.

Klju ne re i:fitoterapija; stilbeni; rizik, procena; kardiovaskularnebolesti; ishrana.

Introduction

Resveratrol, trans-3, 5, 4’-trihydroxy stilbene is a natu-rally occurring phytoalexin present in many different typesof nutrients which we consume on daily basis. Resveratrolwas first isolated from dried roots of Polygonum cuspidatum,as the principal active ingredient. Polygonum cuspidatumand its extract have been used in Japanese and Chinese tradi-tional medicine for treatment of various skin inflammations,cardiovascular and liver diseases, and fungal infections 1, 2.

There are two isoforms of resveratrol: cis- and trans–resveratrol. Trans–resveratrol is biologically active isoform.The main source of resveratrol is grape skin. Also, resvera-trol is present in fruits such as cranberry, lingonberry, bil-berry, mulberry, deer berry, blueberry, sparkleberry, par-tridgeberry, jackfruit, and in a peanut orchid tree, scots pine,corn lily, white hellebore, eucalyptus, spruce etc. (Table1) 3, 4. Resveratrol has anti-cancer and anti-inflammatory ef-fects and beneficial cardiovascular effects 4. There werearound 800 published articles about biological properties ofresveratrol and its health benefits, from 1940 until 2005.From 2005 until nowadays, there are more than 4,000 newstudies with resveratrol on cells, isolated animal organs,animals and humans.

It is well known that resveratrol has beneficial effectson the cardiovascular system. It plays the most importantrole in the epidemiological phenomenon called “Frenchparadox” (existence of cardiovascular risk factors with lowincidence/mortality rates which may attribute to moderateconsumption of red wine) 12, 13. The following will describe

the most important effects of resveratrol on the cardiovascu-lar system.

Table 1The amount of resveratrol found in natural food

Source Amount ofresveratrol

Bilberries ~0.65 μg/g 5

Blueberries ~0.32 ng/g 6Dry grape skin ~24.06 μg/g 7Grapes 0.16–3.54 μg/g 8Peanuts 0.02–1.92 μg/g 9Pistachios 0.09–1.67 μg/g 10

Red wines 01–14.3 mg/L 11

Bioavailability of resveratrol

After oral administration, resveratrol absorbs rapidly(75%) by transepithelial diffusion. It is detected in a 15-minpost-administration and reaches peak concentrations after 30min. Values returned to baseline within 4 h 14. Previously, weshowed that different bile acids micellar solutions improvedresveratrol solubilization 15. The metabolism of resveratrol isextensive in the intestine and liver. Because of intense me-tabolism, an oral bioavailability of resveratrol is less than1%. The major active metabolites of resveratrol are glucuro-nides (trans-resveratrol-3-O-glucuronide) and sulfates (trans-resveratrol-3-sulfate). Also, colonic bacterial metabolismplays an important role in resveratrol metabolism 16. Me-tabolites of resveratrol are eliminated by kidneys.

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How much?

The best source of resveratrol is considered to be redwine and it is generally believed that resveratrol is respon-sible for cardioprotective effects related to red wine con-sumptionn 11, 17. Approximately 300 mL of red wine forman and up to 200 mL for women is the average recom-mended dose (equate to a dose of 15 mg and 10 mg of res-veratrol, repectively). It is well known that resveratrol pro-duces beneficial effects to human health in a dose-dependent manner, by diverse mechanisms. Data aboutdose-dependency of resveratrol in the cardiovascular sys-tem are shown in Table 2 4.

Resveratrol-induced vasorelaxation

Resveratrol relaxes isolated human internal mammaryartery, rat aorta and mesenteric artery (Figure 1) 25–27. Also,there are evidences that resveratrol relaxes mesenteric anduterine arteries of guinea pig and porcine coronary and reti-nal artery 28–30. Rakici et al. 31 have described that resveratrol

effects vascular tone and endothelial function of the humansaphenous vein and internal mammary artery. In addition,resveratrol significantly improves vascular response instreptozotocin-induced diabetic rats 32.

Mechanism of vasodilatation by resveratrol is not welldefined. Resveratrol induces endothelium-dependent and en-

dothelium-independent vasorelaxation. Endothelium-depen-dent mechanisms of relaxation by resveratrol include stimu-lation of endothelial nitric oxide (NO) production by SIRT1-dependent endothelial NO synthase (eNOS) upregulation andSIRT1-dependent eNOS deacetylation. Estrogen receptor(Er )-dependent, ERK1/2-mediated eNOS phosphorylationis stimulated by resveratrol 33. Resveratrol lowers superox-ide-mediated NO inactivation by different mechanisms. Itdecreases expression and activity of vascular nicotinamideadenine dinucleotide phosphate (NADPH) oxidases (NOX)and stimulates expression of superoxide dismutases (SOD),catalase and glutathione peroxidases 34. Thus, oral treatmentwith resveratrol results in endothelium-dependent relaxation.

In the clinical study (double-blind, randomized cross-overstudy) which included 19 obese men and post-menopausalwomen with untreated borderline hypertension, acute con-sumption of resveratrol (30, 90 or 270 mg) increases res-veratrol concentration in plasma and flow-mediated dilationof the brachial artery 35. According to this, it seems that res-veratrol improves endothelial (dys)function.

The endothelium-independent relaxation is probablymediated by different ion channels in the membrane of vas-cular smooth muscle cells, including big Ca2+-activated K+

(BKCa)-channels or voltage-gated calcium channels 36. Also,there are evidences that margatoxin-sensitive smooth musclevoltage-sensitive K+ (Kv) channels play important role in va-

Fig. 1 – Endothelium-independent relaxation of rat mesenteric artery induced by resveratrol precontracted byphenylephrine (PE, 1 M).

Endothelium was removed mechanically by rubbing with a steel wire. Cumulative concentrations of resveratrol were added to the organ-bath (from 0.3 to 100 M).

Table 2Effects of different doses of resveratrol on the cardiovascular system

Doses Effects on cardiovascular system50 nM Induces eNOS activity and activates ERK 18

0.15/0.25 μM Inhibits platelet activation 19

10 μM Improves cardiac functions after ischemia/reperfusion injury 20

Protects the heart from ischemia/reperfusion related injury by making theheart pharmacologically preconditioned 20

25 μM Exerts lesser degree of cardioprotection 20

2.5 mg/kg bw Alleviates cardiac dysfunction in streptozotocin-induced diabetes 21

2.5–5 mg/kg Improves post ischemic cardiac functions 3Reduces myocardial infarction, cardiomyocytes apoptosis 22

22.4 mg/kg Extands the life span, in case of high-calorie diets induce mice, by overex-pressing sirtuin 1 (SIRT1) 23

50–100 μM Inhibition of metabolic activity and cell proliferation 24

1–100 μM Vasodilatation 25

eNOS – endothelial nitric oxide synthase; ERK – extracellular signal regulated kinase.

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sorelaxation induced by resveratrol (Figure 2) 25–27. All stud-ies suggest tissue and species selectivity for resveratrol.

Fig. 2 – The role of potassium channels in vasore-laxation induced by resveratrol.

Resveratrol activates potassium (K+) channels in vascular smooth muscle cellsand induces hyperpolarisation. The change in voltage of membrane of smoothmuscle cells leads to inactivation of sodium (Na+) and calcium (Ca2+) channels

and induces vasorelaxation.

The effects of resveratrol on vascular inflammation

It is well-known that resveratrol has anti-inflammatoryeffect. The major molecular target for the anti-inflammatoryeffects of resveratrol in the vasculature is nuclear factorkappa-beta (NF- ß). Resveratrol inhibits NF- ß and there areseveral mechanisms which are involved in this inhibition.The inhibitory effect of resveratrol on NF- ß may be medi-ated by SIRT1 37. Also, resveratrol inhibits reactive oxygenspecies (ROS)-mediated NF- ß activation by reducing H2O2

levels. Resveratrol inhibits activation of I ß kinases (IKK).IKK kinases are upstream kinases known to activate NF- ß.Those results were obtained in experimental study in skintumor models 38. Also, the transcription of NF- ß is blockedby resveratrol 38, 39.

Antiplatelet effects of resveratrol

Resveratrol has antiplatelet effects. This effect of res-veratrol has been shown on isolated platelets from healthysubjects 40. There is experimental study which describedthat resveratrol has prophylactic effects on portal veinthrombosis in the rat. According to this study, foods con-taining resveratrol can be advised to minimize portal veinthrombosis, at least among patients undergoing liver trans-plantation and displaying certain cardiovascular diseaserisk factors 41. The mechanism of antiplatelet effect of res-veratrol is not completely clear. Resveratrol enhances en-dothelial NO production, NO could diffuse into plateletsand inhibits platelet aggregation by activation of guanylylcyclase and production of cyclic guanosine monophosphate(cGMP). It was described in the isolated human platelets.

The level of cGMP was increased in endothelium-independent manner 40. There are assumptions that res-veratrol enhanced platelet NO production and improvedNO bioactivity due to the reduction of oxidative stress.Also, resveratrol is a potent inhibitor of cyclooxygenase 1(COX-1). The inhibition of COX-1 is irreversible and non-competitive 42. On the other hand, Kundu et al. 38 2006 de-scribed that resveratrol inhibited both COX-1 and COX-2.There are some evidences that resveratrol inhibited throm-boxane synthesis by inhibition of a pathway involving p38mitogen-activated protein (MAP) kinase 19.

Resveratrol and atherosclerosis

In an experimental study, which included rabbits onthe hypercholesterolemic diet, resveratrol had significantanti-atherogenetic effects 43. The effect of resveratrol sup-plements, with regard to the modulation of lipid profiles,cholesterol synthesis and anti-atherogenesis, were exam-ined in apo E-deficient (apoE(-/-)) mice fed a normal diet.The concentration of total cholesterol (total C) and low-density lipoprotein cholesterol (LDL-C) in plasma was sig-nificantly lower in the resveratrol-supplemented groupscompared to the control group of mice 44. The effect of res-veratrol on intimal hyperplasia after endothelial denudationwas examined in experimental rabbits. The results of thisexamination suggest that this polyphenol might have clini-cal potential in prevention and treatment of restenosis afterangioplasty 45. Also, this compound may inhibit lipid per-oxidation by scavenging free radicals. The mechanismwhich is, also, involved in anti-atherogenetic effect of res-veratrol is inhibition of vascular inflammation (describedabove). Resveratrol inhibits proliferation and migration ofthe vascular smooth muscle cell. There is evidence thatresveratrol blocks oxidized LDL-induced proliferation ofsmooth muscle cell. Actually, resveratrol inhibits themammalian target of rapamycin (mTOR) mitogenic sig-naling pathway 46. According to this, it is obvious that allthe described mechanisms might be involved in an anti-atherogenetic effect of resveratrol.

Resveratrol and diabetes

In animal studies, resveratrol decreases blood glucoseand protects pancreatic ß cells from oxidative damage 47. Itbinds to sulfonylurea receptor and block pancreatic adeno-sine-5'-triphosphate (ATP)-sensitive K+ channels. Also, res-veratrol displaced binding of glibenclamide, the drug whichblocks ATP-sensitive K+ channels in ß cells 48. Resveratrolstimulated secretion of insulin in ß cell insulinoma lines 49. Inthe presence of resveratrol, the amplifying pathway of insu-lin secretion, independent of the closure of ATP-sensitive K+

channels in ß cells, was reported 50.In development of type 2 diabetes, the most critical

factor is insulin resistance. It is well known that SIRT1 hasinvolved in the processes of glucose metabolism and insulinsecretion. Increased expression of SIRT1 improves insulinsensitivity. Resveratrol is potent activator of SIRT1. Also, it

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attenuates high fat diet-induced insulin resistance in vivo, indose of 2.5 mg/kg/day 51.

The effect of resveratrol on energy metabolism andmetabolic profile was investigated in randomized double-blind, crossover study which included 11 healthy, obese mentreated with placebo or with resveratrol 150 mg/day for 30days. The conclusion of this study was that resveratrol in-duced metabolic changes in the obese humans, mimickingthe effects of calorie restriction. Resveratrol decreases intra-hepatic lipid content, circulating glucose, triglycerides andinflammation markers 52.

Resveratrol and oxidative stress

The direct antioxidant effect of resveratrol is notprominent. Well established antioxidants, such as ascorbateand cysteine are more potent than resveratrol 53. Resveratrolhas been shown to be a scavenger of hydroxyl, superoxide,metal-induced radicals and H2O2. In cardiovascular tissues,resveratrol induces antioxidant enzymes. The molecularmechanisms of induction of antioxidant enzymes by res-veratrol are not completely understood. Studies have demon-strated that SIRT1 and the nuclear factor E2-related factor-2(Nrf2) play crucial roles in this process. Resveratrol inducedSOD2 upregulation in cultured human coronary arterial en-dothelial cells. Such upregulation can be blocked by smallinterfering RNA (siRNA)-mediated knockdown of SIRT1.An overexpression of SIRT1 leads to SOD2 upregulation.Nrf2 is transcription factor involved in the regulation of anumber of ROS detoxifying enzymes. In Nrf2-dependentmanner, in cultured endothelial cell, resveratrol inducedNAD(P)H: quinine oxidoreductases (NQO1), heme oxygen-ase-1 (HO-1) and c-glutamylcysteine synthetase (GCLC).The listed enzymes are rate-limited for glutathione synthe-sis. Also, resveratrol inhibits ROS production 54. Treatmentwith resveratrol reduces the expression of NOS in the heartof hypercholesteroemic mouse, as well as mono-nitrogenoxides in the aorta of trauma hemorrhagic rats 55, 56. The ac-tivity of the NADPH oxidase enzyme complex is reduced byresveratrol 57.

Resveratrol and heart

According to numerous animal studies, proposed anti-ischemic mechanisms of resveratrol include: coronary vaso-dilatation, inhibition of atheroma formation, metabolic pro-tection and less ischemic-reperfusion injury. In addition, res-veratrol (5 μM/L) inhibited growth of cardiac fibroblastsstimulated by angiotensin II, epidermal growth factor andtransforming growth factor , which are essential in cardiacfibrosis and heart failure 12. Zheng et al. 13 demonstrated an-tiarrhythmic effect of resveratrol. In the papillary muscles ofguinea pig heart, resveratrol shortened duration of actionpotential and decreased velocity of phase 0 depolarization.Also, it inhibited delayed after depolarization and triggeredactivity. These effects were due to a decrease of calcium in-flux and intracellular calcium concentration.

Conclusion

Cardioprotection includes all the described effects ofresveratrol. The most important evidence for cardioprotec-tion rendered by resveratrol comes from in vivo studies car-ried out on animal models of chronic heart disease that re-sulted in heart dysfunction. Those include hypertension, obe-sity, metabolic syndrome, type I diabetes, type II diabetes,viral cardiomiopathy, toxin cardiomiopathy and aging.

According to the presented results, the cardioprotectiveeffect of resveratrol is obvious. It is complex and not welldefined. It is necessary to emphasize that all positive effectsof resveratrol were demonstrated mainly in in vitro studiesand in studies with experimental animals, while quality clini-cal studies are lacking.

Further clinical studies are necessary in order to definepharmacokinetics, efficacy, adequate therapeutic doses, toler-ability and possible interactions of resveratrol with other drugs.

Acknowledgments

This work was supported by the Ministry of Education,Science and Technological Development of the Republic ofSerbia (Project No TR 31020).

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Received on June 13, 2012.Revised on July 15, 2012.

Accepted on August 2, 2012.