ArticlePDF AvailableLiterature Review

Impact of Red Wine Consumption on Cardiovascular Health

May 2017
Current Medicinal Chemistry 24(19)

May 2017
24(19)

DOI:10.2174/0929867324666170518100606

Authors:

Luca Liberale

University of Zurich

Aldo Bonaventura

Ospedale di Circolo e Fondazione Macchi Varese

Fabrizio Montecucco

Università degli Studi di Genova

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Background: The devastating effects of heavy alcohol drinking have been long time recognized. In the last decades, potential benefits of modest red wine drinking were suggested. In European countries in which red wide intake is not negligible (such as France), the association between cholesterol and cardiovascular (CV) risk was less evident, suggesting the action of some protective molecules in red wine or other foods and drinks. Methods: This narrative review is based on the material searched for and obtained via PubMed up to May 2016. The search terms we used were: "red wine, cardiovascular, alcohol" in combination with "polyphenols, heart failure, infarction". Results: Epidemiological and mechanistic evidence of a J-shaped relationship between red wine intake and CV risk further supported the "French paradox". Specific components of red wine both in vitro and in animal models were discovered. Polyphenols and especially resveratrol largely contribute to CV prevention mainly through antioxidant properties. They exert beneficial effects on endothelial dysfunction and hypertension, dyslipidemia, metabolic diseases, thus reducing the risk of adverse CV events such as myocardial infarction ischemic stroke and heart failure. Of interest, recent studies pointed out the role of ethanol itself as a potential cardioprotective agent, but a clear epidemiological evidence is still missing. The aim of this narrative review is to update current knowledge on the intracellular mechanism underlying the cardioprotective effects of polyphenols and ethanol. Furthermore, we summarized the results of epidemiological studies, emphasizing their methodological criticisms and the need for randomized clinical trials able to clarify the potential role of red wine consumption in reducing CV risk. Conclusion: Caution in avowing underestimation of the global burden of alcohol-related diseases was particularly used.

Phenol structural unit and flavonoids. Phenolic ring, also known as carbolic acid (C6H5OH). This molecule consists of a phenyl group (−C6H5) bonded to a hydroxyl group (−OH) (A). Different subclasses of the polyphenols flavonoids: proanthocyanidin, anthocyanins, and flavonols. (B)

…

Chemical structures of trans-and cis-resveratrol. COX-1: cyclooxygenase-1; GLP-1: glucagon-like peptide 1; NO: nitric oxyde. R/I: reperfusion/njury; SIRT1: sirtuin-1.

…

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Current Medicinal Chemistry, 2017, 24, 1-21 1

REVIEW ARTICLE

Impact of Red Wine Consumption on Cardiovascular Health

Luca Liberalea#, Aldo Bonaventuraa#, Fabrizio Montecuccoa,b,c*, Franco Dallegria,b and

Federico Carbonea

aFirst Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132

Genoa, Italy; bIRCCS AOU San Martino - IST, Genova, 10 Largo Benzi, 16132 Genoa, Italy; cCentre of Excellence for

Biomedical Research (CEBR), University of Genoa, 9 viale Benedetto XV, 16132 Genoa, Italy

A R T I C L E H I S T O R Y

Received: November 11, 2016

Revised: March 05, 2017

Accepted: March 05, 2017

DOI:

10.2174/0929867324666170518100606

Abstract: The devastating effects of heavy alcohol drinking have been long time recog-

nized. In the last decades, potential benefits of modest red wine drinking were suggested.

In European countries in which red wide intake is not negligible (such as France), the as-

sociation between cholesterol and cardiovascular (CV) risk was less evident, suggesting

the action of some protective molecules in red wine or other foods and drinks. Epidemiol-

ogical and mechanistic evidence of a J-shaped relationship between red wine intake and

CV risk further supported the “French paradox”. Specific components of red wine both in

vitro and in animal models were discovered. Polyphenols and especially resveratrol

largely contribute to CV prevention mainly through antioxidant properties. They exert

beneficial effects on endothelial dysfunction and hypertension, dyslipidemia, metabolic

diseases, thus reducing the risk of adverse CV events such as myocardial infarction

ischemic stroke and heart failure. Of interest, recent studies pointed out th e role of ethanol

itself as a potential cardioprotective agen t, but clear epidemiological evidence is still

missing. The aim of this narrative review is to update current knowledge on the intracellu-

lar mechanism underlying the cardio protective effects of polyphenols and ethanol. Fur-

thermore, we summarized the results of epidemiological studies, emphasizing their meth-

odological criticisms and the need for randomized clinical trials able to clarify the poten-

tial role of red wine consumption in reducing CV risk. Caution in avowing underestima-

tion of the global burden of alcohol-related diseases was particularly used.

Keywords: Alcohol, ethanol, flavonoids, polyphenols, red wine, resveratrol

1. INTRODUCTION

More than twenty years ago, a lower incidence of

cardiovascular (CV) disease was observed in the

French population, despite their dietary intake of satu-

rated fats [1]. This unexpected observation, also known

as “French paradox”, raised the interest on the potential

protective effects of red wine on CV health. The find-

ing of a U-/J-shaped relationship between red wine

*Address correspondence to this author at the First Clinic o f Inter-

nal Medicine, Department of Internal Medicine, IRCCS AOU San

Martino - IST, and Centre of Excellence for Biomedical Research

(CEBR), University of Genoa. 6 viale Benedetto XV, 16132 Genoa,

Italy; Tel: +39 010 353 86 94; Fax: +39 0101 353 86 86;

E-mail: fabrizio.montecucco@.unige.it

#These authors equally contributed as the first author to this work

intake and CV risk was the first epidemiological evi-

dence explaining the “French paradox” [2]. Further

studies on red wine composition focused on polyphe-

nols contained in red wine and their antioxidant proper-

ties [3]. Several in vitro and animal studies investigat-

ing the polyphenol content in red wine (and partially in

the beer) strongly suggested their active protective role

in CV prevention [4]. More recently, also the Mediter-

ranean diet, characterized by moderate intake of red

wine during meal, has been associated with some

benefit in the prevention of CV diseases and cancer [5].

In this context, both the European Society of Cardiol-

ogy and the European Atherosclerosis Society sug-

gested a moderate alcohol consumption in non-

abstainers with normal levels of triglycerides (TAG),

2 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Liberale et al.

defined as up to 20-30 g/day for men and 10-20 g/day

for women [6, 7].

In addition, WHO recently defined light, moderate

and heavy drinkers, as reported in Table 1 [8].

Table 1. Alcohol consumption definition based on

drinking quantity and frequ ency.

LIGHT DRINKER

≤ 1 drink/day

MODERATE DRINKER

2-3 drinks/day

HEAVY DRINKER

≥ 4 drinks/day

standard drink equivalent 12.5 g of absolute ethanol

100 ml wine (13% alc/vol)

240 ml regular beer (4.9% alc/vol)

33 ml spirit (40% al/vol)

Nevertheless, clinical studies have not always con-

firmed experimental evidence. These contrasting re-

sults may be due to different confounding factors such

as age, gender, comorbidities and drinking pattern. In

addition, it should also consider that polyphenolic me-

tabolites reach very low concentrations in the blood-

stream. On this basis, the aim of this narrative review is

to update the knowledge of different classes of poly-

phenols contained in red wine, focusing on experimen-

tal and clinical evidence. In addition, potential benefi-

cial effects of low-moderate ethanol consumption will

be discussed. Finally, epidemiological evidence sup-

porting a clinical association between red wine intake

and low CV risk will be critically discussed.

2. POLYPHENOLS

2.1. Structure, Biosynthesis, and General Properties

Grapes contain a lot of polyphenols, a large group

of compounds having an aromatic ring(s), character-

ized by the presence of one or more hydroxyl groups

with varying structural complexities (Fig. 1A). Poly-

phenols are classified as flavonoids and non-flavonoid

compounds. Flavonoids include proanthocyanidins an-

thocyanins and flavonols. Non-flavonoid polyphenols

include stilbene (also known as resveratrol), but also

saponin, curcumin, and tannins. Quantification of die-

tary intake of polyphenols is quite difficult [9, 10], and

this is due to the large variability of the phenolic source

and bioavailability [11]. In this regard, physical proper-

ties of the solution are a major determinant of polyphe-

nol bioavailability. Thus, as compared with wine, the

high alcohol content of whiskey improves polyphenol

absorption [12], whereas absorption of flavonols was

demonstrated to be higher in onion or black tea [13].

The major polyphenols contained in red wine are an-

thocyanin and catechins [14], but the polyphenolic

composition is largely dependent on soil composition,

geographic position, plant disease and farming tech-

nique. Biological activities of polyphenols are depend-

ent on their pharmacokinetic properties. Lipophilic pro-

perties of procyanidins, quercetin and flavonols pro-

mote a passive transport through enteric cells mem-

branes, whereas absorption of hydrophilic polyphenols

(ingested as esters, glycosides, or polymers) require

enzymatic hydrolysis [15] and conjugation by sul-

fation, methylation and glucuronidation [16]. However,

all classes of polyphenols undergo hepatic metabolism,

so that serum concentrations of original compounds are

very low (usually less than 1µmol/l), and circulating

polyphenols are mostly active metabolites.

2.2. Flavonoid Polyphenols

2.2.1. Flavonoid Polyphenol-Mediated Signaling

Polyphenols have beneficial effects on different bio-

logical pathways. In addition to promoting free-radical

scavenging, metal chelation, and enzyme modulation,

they have major effects on cell cycle, xenobiotic me-

tabolism, immune-related factors and transcription

(about 2200 transcripts have been estimated to be di-

rectly influenced by flavonoids) [17]. Among polyphe-

nols, flavonoids mediated the most of the anti-oxidant

properties ascribed to red wine, including inhibition of

lipid oxidation, peroxide generation and lipid peroxida-

tion [18-20]. The flavonoid quercetin was also shown

to enhance neuronal resistance to age-related diseases

in mice via AMPK activation [21]. Furthermore, quer-

cetin may prevent adipogenesis by inducing apoptosis

of 3T3-L1 pre-adipocytes via AMPK-mediated activa-

tion of ERK and JNK pathways [22]. However, a sig-

nificant reduction of fat accumulation in mature adipo-

cytes was observed only with a very high dose of quer-

cetin [23]. Alongside AMPK, also, sirtuins (SIRT)

have been described as flavonoid target. In particular,

polyphenol-dependent SIRT-1 activation has been

shown to increase brain and muscle mitochondrial bio-

genesis [24, 25], as well as to suppresses endothelial

oxidative injuries induced by oxLDL [26]. Finally, die-

tary quercetin in mice has also been reported to reduce

macrophage infiltration and inflammation in adipose

tissue, likely through an AMPK/SIRT1-mediated

mechanism [27].

An anti-estrogenic role of polyphenols has been

proposed but it still need fully elucidation [28]. An es-

trogen receptor (ER)-dependent activation of endothe-

lial nitric oxide synthase (eNOS) was first shown in

Impact of Red Wine Consumption on Cardiovascular Health Current Medicinal Chemistry, 2017, Vol. 24, No. 00 3

bovine aortic endothelial cells exposed to black tea

polyphenols [29]. Then, ER-mediated benefits on endo-

thelial activity have been demonstrated for several spe-

cific flavonoids such as delphinidin, epicatechin, sy-

ringic acid, apigenin, malvidin and ellagic acid [30,

31]. However, these results were not later confirmed in

cultured endothelial cells of rats [32], and also a recent

study on ovariectomized mice described pro-angio-

genic properties of red wine polyphenols as independ-

ent of ERα activation [33].

2.2.2. Flavonoid Polyphenol in Endothelial Dysfunc-

tion and Hypertension

Regardless of the mechanism, the protective role of

red wine polyphenols on CV health is largely related to

the up-regulation of the eNOS activity. Polyphenols-

induced vasorelaxation has been demonstrated in dif-

ferent experimental models such as rat aortic rings and

mesenteric arteries [34-36]. In later studies on the iso-

lated porcine coronary artery, electron spin resonance

Fig. (1). Phenol structural unit and flavonoids. Phenolic ring, also known as carbolic acid (C6H5OH). This molecule con-

sists of a phenyl group (−C6H5) bonded to a hydroxyl group (−OH) (A). Different subclasses of the polyphenols flavonoids:

proanthocyanidin, anthocy anins, and flavonols. (B)

4 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Liberale et al.

spectroscopy analysis demonstrated an enhanced endo-

thelial generation of nitric oxide (NO) and endothe-

lium-derived hyperpolarizing factor, as a result of PI3-

kinase/Akt and Src phosphorylation [37, 38]. There-

fore, anti-hypertensive effects of polyphenol-rich com-

pounds were observed in various animal models. Red

wine polyphenols have been shown to reduce arterial

blood pressure in angiotensin II-induced hypertensive

mice, together with preventing vascular superoxide

anion production and NADPH oxidase subunit expres-

sion [39]. Similar beneficial results have been also ob-

served in hypertensive rats treated with specific fla-

vonoid compounds such as provinol, proanthocyanid-

ins, and catechins [40-42].

2.2.3. Anti-atherosclerotic Properties of Flavonoid

Polyphenol

Aside from preventing endothelial dysfunction, red

wine flavonoids were reported to exert anti-atheroscle-

rotic effects in different experimental studies. Treat-

ment with quercetin in diet-induced atherosclerotic

hamsters was associated with significant reduction of

aortic fatty streaks and improved lipid profile, charac-

terized by low total plasma cholesterol and increased

apolipoprotein (apo)A-I levels [43]. Furthermore, the

administration of flavonoids-rich grape juice has been

shown to reduce the detrimental effects of hypercholes-

terolemic diet in rabbit, by reducing serum cholesterol,

blood pressure, and platelet aggregation [44]. Interest-

ingly, this intriguing effect of flavonoids on platelet

activity was confirmed in two clinical studies. Quer-

cetin and catechin showed a synergic effect in sup-

pressing collagen-induced platelet aggregation and

platelet adhesion to collagen [45], whereas platelet in-

cubation with diluted purple grape juice was associated

with increased NO release and decreased superoxide

production [46].

2.2.4. Flavonoid Polyphenols in Metabolic Diseases

and Inflammation

Anti-oxidant properties of polyphenols have also

been shown to be effective in metabolic diseases. By

suppressing NADPH oxidase activity, polyphenol-rich

grape extract prevents the development of insulin resis-

tance, hypertension, cardiac hypertrophy and endothe-

lial dysfunction in high fructose-fed rats [47]. Simi-

larly, through the suppression of NADPH oxidase ac-

tivity, catechin normalized blood pressure and pre-

vented endothelial dysfunction and insulin resistance in

pre-diabetic rat (Otsuka Long-Evans Tokushima Fatty

[OLETF] model) [48], whereas provinol improved car-

diac performance in Zucker fatty rats, as evidenced by

an increase in left ventricular fractional shortening and

cardiac output associated with decreased peripheral

arterial resistances [49]. On the other hand, many bene-

ficial effects of polyphenols on CV health may be as-

cribed to their anti-inflammatory properties. Alhough,

anti-inflammatory properties of polyphenols are in part

associated with antioxidant activity, they also showed

capacity to directly modulate cytokine expression.

Treatment with procyanidins has been shown to sup-

press the release of interleukin (IL)-6 and monocyte

chemo-attractant protein-1 from adipocyte and macro-

phage-like cells, in addition, to reduce the plasmatic

levels of C-reactive protein (CRP) and IL-6 in high fat-

fed rats [50].

2.2.5. Flavonoid Polyphenols and Cardiovascular

Risk: Clinical Evidence

Alongside experimental evidence, many clinical

studies investigated the potential protective role of

polyphenols on CV health [51]. In healthy subjects, the

endothelial function assessed by flow-mediated dilata-

tion (FMD) increased after the consumption of 3 mL/kg

or two glasses of red wine with or without alcohol [52-

54]. This effect was moreover amplified in a synergis-

tic manner, by combining red wine with other compo-

nents of Mediterranean diet, such as olive oil [55].

Beneficial effects on FMD were also observed after the

administration of non-alcoholic beverages or dark cho-

colate, thus emphasizing the role of polyphenols [56-

59]. Interestingly, these results have been confirmed in

several cohorts with high CV risk such as post-

menopausal women [60], smokers [61-63], and meta-

bolic disorders (hypercholesterolemia, diabetes, over-

weight) [61-67]. Finally, protective effects of polyphe-

nols on vascular function (defined as increased FMD

and reduced intima-media thickness) have been ob-

served after administration of black tea, epigallocate-

chin gallate-rich green tea, and red grape juice pome-

granate juice in patients with hypertension [68-71] and

established coronary heart disease [72-77].

2.3. Resveratrol and Non-flavonoid Polyphenols

Resveratrol (C14H12O3; 3,5,4’-trihydroxystilbene)

is a natural polyphenolic compound characterized by two

phenol rings linked by a styrene double bond (Fig. 2).

It is produced by a lot of plant species and fruits,

such as purple grapes, blueberries, mulberries, cranber-

ries, rhubarb, peanuts, groundnuts, and pines [78-80].

Grapes are the most important source of resveratrol for

humans, since the compound is present in the wine, in

particular, the red wine (concentration between 1 and

Impact of Red Wine Consumption on Cardiovascular Health Current Medicinal Chemistry, 2017, Vol. 24, No. 00 5

14 mg/L) [81]; their highest concentration is found in

the skin and seeds of grapes (50-100 µg/g equal to 5-

10% of their biomass) [82]. The main enzyme respon-

sible for resveratrol biosynthesis is stilbene synthase

(STS), which is rapidly activated in response to exoge-

nous or environmental stress factors, such as injury,

ultra-violet irradiation, and fungal attack [83]. STS

catalyzes 3 condensation reactions between coumaroyl-

coenzyme A (CoA) and 3 molecules of malonyl-CoA

via cleavage of 3 carbon dioxide molecules and the loss

of the terminal carboxyl group, leading to the produc-

tion of the C14 molecule resveratrol [83, 84]. Resis-

tance against stress factors is warranted if the phytoa-

lexin accumulation occurs rapidly on the exposed site.

Typically, resveratrol levels peak 24 hours after stress

exposure and decline after 42-72 hours following stil-

bene oxidase activation [82, 85]. Resveratrol presents

with pleiotropic beneficial effects on health including

antioxidant, anti-inflammatory, cardioprotective and

anti-tumor properties [86].

2.3.1. Resveratrol-mediated Signaling and Endothe-

lial Dysfunction

In animal models of hypertension, diabetes, and hy-

percholesterolemia, oral treatment with resveratrol re-

sulted in the improvement of the endothelium-depen-

dent relaxation [86-88]. Similar results were found in

overweight/obese men and post-menopausal women

with untreated, borderline hypertension, who showed

an increase in the FMD of the brachial artery [89]. The

enhancement of the endothelial function is mostly due

to the eNOS-mediated NO generation through at least

seven mechanisms [90]: (i) the stimulation of eNOS

gene transcription and the increase in the eNOS mes-

senger ribonucleic acid stability, partly due to the up-

regulation of eNOS expression by the SIRT-1 [91, 92];

(ii) the stimulation of eNOS phosphorylation mediated

by the estrogen receptor α and the signaling pathway

concerning the α-subunit of G-protein, caveolin (Cav)-

1, the tyrosine kinase Src, and the mitogen-activated

protein kinase (MAPK)/extracellular signal-regulated

kinase 1/2 [93, 94]; (iii) the induction of SIRT-1-

mediated deacetylation of lysines 496 and 506 in the

calmodulin-binding domain of eNOS [95]; (iv) the de-

crease of intracellular levels of the endogenous eNOS

inhibitor asymmetric dimethylarginine [96]; (v) the

reduction of Cav-1 levels and Cav-1/eNOS interactions

[94, 97]; (vi) the blockage of eNOS uncoupling by

augmenting the eNOS cofactor tetrahydrobiopterin

(BH4) intracellular levels and the prevention of the

BH4 oxidation by decreasing the oxidative stress [98];

and (vii) the amelioration of NO bioactivity via the in-

hibition of superoxide-mediated NO inactivation [99].

On the basis of controversial results in some animal

studies, resveratrol cannot be considered a direct

SIRT1 activator [100-102], although an enzymatic ac-

tivation of SIRT1 by resveratrol in vivo cannot be kept

out [103, 104]. In this regard, resveratrol effects might

also be mediated by an up-regulation of SIRT1 expres-

sion [92, 105]. Moreover, the SIRT1 activation by res-

veratrol in vivo is thought to be an indirect effect medi-

ated by AMPK as an upstream target [106]. Overall,

Fig. (2). Chemical structures of trans- and cis-resveratrol. COX-1: cyclooxygenase-1; GLP-1: glucagon-like peptide 1; NO:

nitric oxyde. R/I: reperfusion/njury; SIRT1: sirtuin-1.

6 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Liberale et al.

the increased release of endothelial NO induced by res-

veratrol is protective for blood vessels because of its

antihypertensive (in terms of vasodilation), anti-throm-

botic (by the inhibition of platelet aggregation), and anti-

atherosclerotic (avoiding leukocyte adhesion to vascu-

lar endothelium, reducing the low-density lipoprotein

(LDL) oxidation, and inhibiting vascular smooth mus-

cle cell proliferation) characteristics.

2.3.2. Resveratrol, Vascular Inflammation, and Oxi-

dative Stress

Resveratrol treatment was found to block the pro-

duction of reactive oxygen species (ROS) induced by

tumor necrosis factor (TNF)-α, activation of NF-κB,

intercellular adhesion molecule-1, and IL-6 [107, 108].

Given that NF-κB is believed the most important target

of resveratrol, the putative mechanisms of inhibition

are the following: (i) reduction of H2O2 levels; (ii) in-

hibition of the phosphorylation of IκB, which is re-

sponsible for the NF-κB activation; (iii) the inhibition

of p65 phosphorylation, that is necessary for the tran-

scriptional activation of NF-κB; (iv) the possible

deacetylation of the p65 subunit of NF-κB by SIRT1

[109-111]. Resveratrol was shown to be an ROS scav-

enger, even if its direct antioxidant activity is relatively

poor and can be referred to the up-regulation of the en-

dogenous cellular antioxidant systems [112, 113]. Res-

veratrol may induce antioxidant enzymes: superoxide

dismutase (SOD)1, SOD2 and SOD3 in endothelial

cells, and SOD2 in cardiac myoblasts [114-116]. Res-

veratrol also increases the expression of thioredoxin

(Trx)-1 and -2, glutaredoxin (Grx)-1 and -2, heme oxy-

genase (HO)-1, NADPH, quinone oxidoreductases, and

γ-glutamylcysteine synthetase, the rate-limiting en-

zyme for glutathione synthesis [117-120]. Although

SIRT1 and nuclear factor-E2-related factor-2 (Nrf2)

play a critical role in this process, molecular mecha-

nisms involved in the induction of antioxidant enzymes

by resveratrol are not yet fully known. Moreover, res-

veratrol was demonstrated to decrease oxidative stress

by inhibiting ROS production. In the heart of hyper-

cholesterolemic mice and in the trauma-related hemor-

rhagic aorta of rats, the expression of NADPH oxidase

(NOX)1, NOX2, and NOX4 was reduced by resvera-

trol treatment [98, 121]. Resveratrol also reduces the

activity of the NOX enzyme complex by hitting the

regulatory subunits [122]. Finally, in platelets, protein

kinase C (PKC)-mediated phosphorylation of p47phox

is blocked by resveratrol [123].

2.3.3. Resveratrol and Hypertension

Anti-hypertensive effects of resveratrol have been

studied in animal models of hypertension and hyper-

tension combined with insulin resistance [124, 125].

High doses of resveratrol lowered high pressure and

prevented cardiac hypertrophy in two different hyper-

tensive animal models [126, 127], whereas some stud-

ies underscored the ability of resveratrol to reverse car-

diac hypertrophy and contractile dysfunction [128,

129]. With regard to clinical studies, a meta-analysis

with 247 subjects recently showed that only high doses

of resveratrol (≥150 mg per day) were able to signifi-

cantly reduce blood pressure [130]. The mechanisms

underlying the anti-hypertensive properties of resvera-

trol are mainly endothelium-dependent, characterized

by increased NO availability due to an up-regulation of

eNOS strictly linked to AMPK, SIRT1, and Nrf2 acti-

vation [124]. On the other hand, the inhibition of vas-

cular smooth muscle cells contractility, via AMPK ac-

tivation, represents an endothelium-independent mech-

anism [131].

2.3.4. Resveratrol and Atherosclerosis

In the hypercholesterolemic rabbit model, resvera-

trol reduced the size, density, and mean area of athero-

sclerotic plaque [132]. It was also shown to decrease

plasma TAG and LDL-cholesterol (LDL-c) levels, and

increase HDL-cholesterol (HDL-c) [133], in addition to

enhancing the expression of the LDL receptors in hepa-

tocytes in vitro [134]. However, clinical studies have so

far provided controversial results [135]. However, res-

veratrol was shown to lower LDL-c in diabetic patients

[136] as well as to reduce plasma TAG in obese men

[137] and smokers [137]. Notably, in high CV risk pa-

tients under statin treatment for primary prevention,

resveratrol was shown to reduce oxidized LDL and

LDL-c [138]. Different mechanisms may contribute to

the anti-atherosclerotic properties of resveratrol: stimu-

lation of NO production [139]; inhibition of LDL oxi-

dation [140]; inhibition of smooth muscle cell prolif-

eration [141, 142]. A possible contribution of SIRT1 in

blocking atherogenesis is also to be considered, but

further studies are required to clarify this issue [91].

2.3.5. Resveratrol and Diabetes

Resveratrol as also showed to reduce blood glucose

and to protect pancreatic β-cells from oxidative damage

in animal studies [143], to attenuate diabetic vascular

complications [144], and to decrease diabetic cardio-

myopathy [145]. In obese men treated with resveratrol

(150 mg per day) for 30 days, modest metabolic

changes, including insulin resistance, have been in-

duced [137]. The anti-hyperglycemic effects of res-

veratrol are likely to be dependent on increasing glu-

cose uptake by peripheral tissues, as a result of en-

Impact of Red Wine Consumption on Cardiovascular Health Current Medicinal Chemistry, 2017, Vol. 24, No. 00 7

hanced glucose transporter-4 translocation of to the

plasma membrane [146] and the increase in glycogen

storage via glycogen synthase and glycogen phos-

phorylase activities [147]. Moreover, resveratrol was

demonstrated to potentiate the glucose-stimulated insu-

lin secretion in β-cells through SIRT1-dependent

mechanisms [148], in addition to potentiating the oxi-

dation of fatty acids and decrease their synthesis via

AMPK activation [149]. Therefore, SIRT1 and AMPK

are both crucial also in mediating the effects of resvera-

trol on insulin resistance [150, 151].

2.3.6. Resveratrol and Ischemic Heart Disease

Resveratrol is protective against ischemic cardiac

disease through different mechanisms. First of all, it

prevents myocardial infarction due to the inhibition of

platelet aggregation, in both healthy subjects and in

aspirin-resistant patients [152, 153]. The antiplatelet

effect may be mediated by the NO diffusion into plate-

lets thus activating the guanylyl cyclase and producing

cyclic guanosine monophosphate, by blocking PKC-

mediated phosphorylation, as previously mentioned,

and by inhibiting the pathway involving p38 MAP

kinase leading to a reduced thromboxane synthesis

[123]. Secondly, resveratrol protects the myocardial

tissue from ischemia/reperfusion injury, characterized

by great inflammatory burst [154, 155], precondition-

ing-like effect [117] and regeneration of infarcted

myocardial tissue [156]. In this context, by up-

regulating eNOS expression, resveratrol may determine

an NO-dependent increase of HO-1, both identified as

of preconditioning effect in the ischemic heart [157,

158]. Additional pathways activated by resveratrol may

include those triggered by adenosine receptors A1 and

A3, and cyclic adenosine monophosphate (cAMP) re-

sponse element-binding protein (CREB) [159]. Also

the SIRT1-FOXO1 pathway was supposed to be in-

volved in the anti-apoptotic effect of resveratrol on

heart ischemia [160], as well as in the induction of

autophagy [161]. The regeneration of infarcted myo-

cardium was demonstrated in a resveratrol-pretreated

rat left anterior descending coronary artery occlusion

model by injecting adult cardiac stem cells in the bor-

der zone of the myocardium due to a significant reduc-

tion of oxidative stress, increase in cell survival and

following proliferation of cardiomyocytes [156]. Fur-

thermore, resveratrol was shown to enhance myocar-

dial angiogenesis in the peri-infarct myocardium both

in vivo and in vitro by inducing vascular endothelial

growth factor (VEGF). This effect is regulated by Trx-

1 and HO-1 signaling and has been associated with

early improvement of left ventricular function after

myocardial infarction [117].

2.3.7. Resveratrol and Heart Failure

In experimental studies, pre-treatment with resvera-

trol showed prevention of cardiac hypertrophy and im-

provement of cardiac function [162, 163]. Some clini-

cal benefit of resveratrol administration was also dem-

onstrated in secondary prevention of heart failure [164,

165]. Nevertheless, no clinical evidence supporting a

beneficial role of resveratrol in patients with heart fail-

ure is currently available. Conversely, patients with

stable coronary artery disease treated with resveratrol

demonstrated an improvement of diastolic function af-

ter myocardial infarction [166]. Potential mechanisms

explaining the effects of resveratrol on the pathophysi-

ology of cardiac hypertrophy and heart failure include a

decrease oxidative stress due to increased expression of

SOD2 [116], augmented levels of glutathione, eNOS

un-regulation, AMPK/Akt-mediated inhibition of pro-

tein synthesis [167], improvement of calcium cycling

via SIRT1 [145], and inhibition of hypertrophic gene

expression.

2.3.8. Resveratrol and Stroke

Resveratrol was demonstrated to protect against

ischemic stroke in adult rats, in part by its anti-oxidant

effect on the cerebrovascular endothelium [168]. This

effect might depend on SIRT1 because its inhibition

with sirtinol partially blocked the protection of endo-

thelial cells. [169]. Resveratrol decreased the infarct

size in a rat model of focal cerebral ischemia as well as

neuroprotective effects have been described [170, 171].

The mechanisms of neuroprotection were recently pro-

posed; resveratrol inhibited phosphodiesterases and

regulated the cAMP/AMPK/SIRT1 pathway, which is

responsible for reduced adenosine triphosphate (ATP)

energy consumption during ischemia and so it in-

creased ATP, phospho-AMPK, SIRT1, and cAMP lev-

els [172]. Considering that resveratrol is able to inhibit

cyclooxygenases (COX), such as COX1 and COX2

[173], the in vivo neuroprotection induced by resvera-

trol might be associated with the abrogation of COX2

in the substantia nigra that limits 6-hydroxydopamine-

induced toxicity [174]. Currently, no investigation has

been conducted in stroke patients, even if resveratrol

showed to increase cerebral blood flow in healthy adult

subjects and to enhance cerebrovascular perfusion in

postmenopausal women [175-177]. Nevertheless, res-

veratrol was found as a potential adjuvant of recombi-

nant tissue-type plasminogen activator (r-tPA) in the

treatment of ischemic stroke [178]. It was shown to

inhibit the expression or the activity of metalloprotein-

ase (MMP)-2 and MMP-9 both in cells lines and in

animal models of stroke [179-181]. These properties

8 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Liberale et al.

may favour the extension of the time window for r-tPA

treatment and the clinical improvement in stroke pa-

tients with late treatment. The inhibitory effect of res-

veratrol is especially found when administered together

with r-tPA, this explaining the reduction in brain

ischemia injuries and the positive correlation between

changes in MMP levels and National Institutes of

Health Stroke Scale scores.

3. ETHANOL

Alongside protective effects of polyphenols, nearly

all epidemiological studies reported a J-shaped curve,

whereby light to moderate ethanol consumption was

associated with lower risk of adverse CV events as

compared with abstainers, while heavy drinkers dem-

onstrated an increased risk [182]. More specifically, a

regular light to moderate consumption of ethanol was

shown to decrease by 30-35% the risk of heart disease

in both men and women, regardless of age [183, 184].

This effect was further increased by healthy lifestyle

behaviors, such as Mediterranean diet, smoking absten-

tion, regular physical activity and low body mass index

(<25 Kg/m2) [185, 186]. Similarly, low to moderate

ethanol consumption has been associated with reduced

risk of ischemic stroke [187] and congestive heart fail-

ure [188]. Cardioprotective effect of ethanol has been

ascribed to a synergic effect involving different targets.

3.1. Ethanol and Endothelial Dysfunction

A J-shaped curve was used also to describe the rela-

tionship between endothelial function and ethanol con-

sumption. Specifically, low-moderate alcohol intake

was shown to increase nitric oxide bioavailability, due

to the up-regulation of eNOS as observed in rats [189,

190]. In addition, ethanol may induce the activation of

transient receptor potential vanilloid 1 channels on

perivascular sensory nerve terminal, which promotes

the release of potent vasodilator agent calcitonin gene-

related peptide [191]. Furthermore, the TNF-α-induced

expression of adhesion molecule [192] was shown to

be down-regulated by red wine consumption in vitro

[193]. As result, in both cross-sectional and random-

ized clinical trials moderate alcohol consumption was

shown to improve endothelial function in healthy sub-

jects, either assessed as FMD or coronary flow velocity

reserve [194-196]. Partially related to endothelial func-

tion, chronic low ethanol consumption was also shown

to reduce systolic blood pressure in rats [197], whereas

the results from clinical studies remain controversial. In

this regard, a recent meta-analysis only identified a

trend toward decreased risk of hypertension [198].

3.2. Ethanol and Dyslipidemia

Low-to-moderate ethanol consumption has been re-

ported to modify composition and function of high-

density lipoprotein cholesterol (HDL-c). A rise of

smaller HDL-c associated with increased concentration

of HDL-c apoA-I and apoA-II has been reported [199,

200], alongside an increase of phospholipids and poly-

unsaturated fatty acid content of HDL-c [201]. Func-

tionally, ethanol ingestion may enhance the activity of

HDL-c as reverse cholesterol transport [202-204], as

well as their anti-atherosclerotic and anti-inflammatory

properties. By promoting the conversion of phosphati-

dylcholine to phosphatidyl ethanol (PEth), ethanol in-

creases HDL binding to endothelial cells and modu-

lates the expression of different growth factor and cy-

tokines [205, 206]. Conversely, the effect of ethanol on

LDL-c is controversial. A significant decrease of circu-

lating LDL-c has been reported in two different cohorts

[207, 208] but not confirmed later by The Italian Lon-

gitudinal Study of Aging [209]. Genetic polymor-

phisms of Apo genes [210, 211] and changes in hepatic

cholesterol metabolism due to ethanol (likely involving

hydroxymethylglutaryl-CoA reductase [HMG-CoA]

reductase and proprotein convertase subtilisin/kexin

type 9 [PCSK9]) [212] may potentially explain these

discrepancies but further studies are required. Contrast-

ing results have been reported also for the relationship

between ethanol and TAG. Although a “U-shaped” re-

lationship has been suggested, this hypothesis has not

been yet validated [208]. As for LDL-c, genetic poly-

morphisms of Apo genes may explain inter-individual

variability in the response of TAG to ethanol [210,

213].

3.3. Ethanol and Metabolic Dysfunction

The association between ethanol consumption and

development of type 2 diabetes has been again de-

scribed as a U or J-formed curve in many observational

studies [214]. More recently, several meta-analysis

confirmed this evidence, thus emphasizing the potential

protective effect of ethanol [215, 216]. Low to moder-

ate ethanol consumption has been found to signifi-

cantly improve insulin sensitivity by different mecha-

nisms. As first, ethanol metabolism inhibits the glu-

coneogenesis, shifts the NADH/NAD-ratio, inhibits the

β-oxidation of fatty acids and inhibits glycogenolysis

[217]. Secondly, ethanol may modulate the endocrine

function of adipose tissue, likely by reducing local in-

flammation. Epidemiological studies reported an asso-

ciation between moderate alcohol consumption and

increased serum levels of adiponectin, which is thought

Impact of Red Wine Consumption on Cardiovascular Health Current Medicinal Chemistry, 2017, Vol. 24, No. 00 9

to improve insulin sensitivity by suppression of hepatic

glucose production, increased glucose uptake and fatty

acid oxidation in muscle tissue [218-220]. As potential

additional mechanism, a reduction of circulating CRP

was observed in subjects with light to moderate alcohol

intake, further supporting a potential anti-inflammatory

activity of ethanol [221-223]. Moreover, ethanol was

shown to dose-dependently reduce IL-6, IL-8, TNF-

alpha, and MCP-1 expression in human adipose tissue

in vitro [224].

3.4. Ethanol and Atherothrombosis

Of interest, moderate ethanol consumption was also

shown to have anti-thrombotic properties. A direct in-

hibitory effect on platelet activity has been demon-

strated ex vivo by comparing life-long abstainers and

low moderate-wine drinkers [225]. In addition, moder-

ate ethanol intake has been associated with low plasma

fibrinogen [226] and reduced plasma viscosity [227],

whereas the effect on fibrinolytic activity remains con-

troversial [228]. In line with experimental evidence,

epidemiological studies reported a reduced risk of

ischemic stroke and venous thrombosis in moderate

drinkers as compared with abstainers [229, 230].

3.5. Ethanol and Ischemic/Reperfusion Injury

Finally, the protective effect of ethanol has been

demonstrated in ischemic/reperfusion (I/R) injury [182].

On the one hand, ethanol intake increases the tolerance

of cardiomyocytes by activating cell survival pathways.

Different experimental model of ischemic pre-condi-

tioning emphasized the role protein kinase C, mito-

chondrial KATP channel, and Akt [231-233], resulting

in the de novo synthesis of protective proteins such as

COX-2, heat shock proteins, inducible nitric oxide syn-

thase, and aldehyde dehydrogenase [234, 235]. Fur-

thermore, the up-regulation of aldehyde dehydrogen-

ase-2 induced by ethanol reduced the generation of cy-

totoxic aldehydes such as 4-hydroxynonenal in heart

undergoing I/R injury [236]. On the other hand, ethanol

may prevent microvascular dysfunction after I/R injury

by abrogating P-selectin expression [237], leukocyte-

platelet/endothelial cell interactions [238, 239], ROS

generation [240], capillary no-reflow, mitochondrial

dysfunction [233, 241], release of pro-inflammatory

mediators, and microvascular barrier disruption [242].

4. RED WINE AND CARDIOVASCULAR RISK:

EVIDENCE FROM CLINICAL STUDIES

In the last decades, a large amount of epidemiologi-

cal studies from different countries showed lower CV

mortality associated with alcohol drinking (including

red-wine and partially beer). This effect has been as-

cribed to the high content of non-alcoholic phenolic

compounds with antioxidant and antithrombotic prop-

erties. Partially supporting this hypothesis, a meta-

analysis of 13 studies including 209,418 subjects

showed a reduced relative risk of CV disease associ-

ated with red/white wine intake as compared with ab-

stainers (RR 0.68 [95% CI 0.59-0.77]) [243]. In the

same study, reduced RR (0.78 [95% CI 0.70-0.86]) was

also associated with moderate beer consumption. How-

ever, a clear inverse relationship between the amount

of beer intake and vascular risk was not suggested. Co-

stanzo et al., who also reported a J-shaped relationship

between different amounts of wine intake [244], ob-

served the same results. However, a significantly lower

risk of CV disease has been also reported for beer and

spirits in other meta-analyses [245-247]. Of interest,

drinking pattern characterized by regular daily light

drinking has been also observed to have a substantial

protective role in diabetes [248], coronary artery dis-

ease [249], hypertension [250] and overall mortality

[251]. On the other hand, several epidemiological

pieces of evidence suggested that ethanol rather poly-

phenols might be the primary mechanism involved in

cardioprotection (Table 2) [252-265].

4.1. Red Wine and Coronary Heart Disease

In this context, the potential association between red

wine and CAD remains high controversial, also consid-

ering that no randomized controlled trials have been so

far performed. With this limitation, different clinical

studies suggested a beneficial effect of moderate red

wine intake on vascular function [252-255], whereas

only a small study failed to demonstrate a vaso-

protection induced by red wine intake [256] (Table 2).

However, those small clinical studies failed to clarify

the primary mechanisms involved in vascular protec-

tion. The lack of difference observed between red and

white wine administration, as reported by Whelan and

coll., might suggest a pivotal role of ethanol in vascular

prevention [252]. Conversely, Lekakis and coworkers

later emphasized the role of red grape polyphenol ex-

tract in increasing FMD [253], whereas Karatzi et al.

reported no difference between the administrations of

regular or dealcoholized red wine [254].

4.2. Red Wine and Metabolic Diseases

Some evidences supports a role of red wine in pre-

venting metabolic diseases (Table 2). As emerged from

PREDIMED trial, moderate red wine intake, assessed

by food-frequency questionnaire was associated with

reduced prevalence of metabolic syndrome and lower

10 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Liberale et al.

Table 2. Randomized clinical trials investigating the effects of red wine consumption in cardiovascular prevention.

Author

Year

Sample Size

Treatment

Outcome

Coronary artery disease

Whelan et al.

[252]

2004

RCT

14 CAD patients

Red or white wine (4

mL/kg) with the meal

over a period of 30 min.

After 6 hours, FMD of the brachial artery improved

nearly threefold in both groups (p<0.01). No difference

was observed between the two treatment and no detect-

able change in plasma polyphenol levels after either

wine.

Lekakis et al.

[253]

2005

RCT

30 males with

CAD

Red grape polyphenol

extract (600 mg) di s-

solved in 20 ml of w ater

or placebo (water 20 ml).

Intake of the red grape polyphenol ex tract increased

FMD as compared to baseline and placebo (p<0.01 for

both).

Karatzi et al.

[254]

2005

cross-over trial

15 patients CAD

Regular or dealcoholized

red wine (250 ml).

Both regular and dealcoholized red wine decreased AIx

by 10.5% (p<0.01) and 6.1% (p=0.01), respectively.

Also a decrease in peripheral and central diastolic BP

was observed for both treatments (p=0.03 for both),

whereas peripheral systolic BP remained unaltered in

both groups.

Guarda et al.

[255]

2005

RCT

20 patients

treated with PCI

Red-wine (250 ml daily)

or abstinence from alco-

holic beverages.

The endothelium-dependent/independent dilatation ratio

significantly improved in both groups as compared to

baseline. In addition, red wine increase antioxidant activ-

ity as compared to control group (p<0.03).

Marinaccio et al.

[256]

2008

RCT

45 men with

stable CAD

Red wine (180 cc), or gin

(60 cc) or placebo (water

120 cc).

All treatment failed to improve IPC, as expressed by the

warm-up phenomenon on exercise stress testing

Metabolic syndrome

Tresserra-Rimbau

et al.

PREDIMED trial

[257]

2009

Cross-sectional

5801 high CV

subjects

Red wine intake was

recorded using a vali-

dated 137-item FFQ.

Compared with abstainers, moderate red wine drinkers

(≥1 drink/day) had redu ced MetS prevalence (OR 0.56

[95% CI 0 .45-0.68]; p<0.01), and lower waist circum-

ference (OR 0.59 [95% CI 0.46-0.77]; p<0.01), associ-

ated with increased HDL-c, low BP and low fasting

plasma glucose concentrations.

Chiva-Blanch et

al.

[258]

2013

Cross-over trial

67 patients at

high CV risk

Red wine (30 g alco-

hol/d), equivalent

amount of dealcoholized

red wine, and gin (30 g

alcohol/d) for 4 weeks in

a randomized order.

Red wine and dealcoholized red wine decreased mean

adjusted plasma insulin and HOMA-IR. Furthermore,

HDL cholesterol, ApoA-I, and A-II increased after red

wine and gin, whereas Lp(a) decreased after the red wine

administration

Gepner et al.

[259]

2015

RCT

224 patients with

well-controlled

T2DM

Red wine, white wine or

water with dinner for 2

years, associated with

MD.

Red wine significantly increased HDL-c (p<0.01) and

apoA-I (p=0.05) whereas decreased the total-c/HDL-c

ratio (p=0.04). In slow ethanol metabolizer, both red and

white improved glycemic control. Overall, red wine

significantly reduced the number of components of the

metabolic syndrome (p=0.05).

Myocardial infarction

Fernández-Jarne et

al.

[260]

2003

Case-control

study

171 treated sub-

jects vs. 171

controls

Alcohol intake assess-

ment during the previous

year (red win e, sweet

wine, other kinds of

wine, wine during meals,

beer, and spirits),

The risk of AMI was inversely associated with alcohol

intake. This was observed for both wine (OR 0.45 [95%

CI 0.22-0.93]) and other alcoholic beverages (OR 0.46

[95% CI 0 .22-0.94]).

(Table 2) contd….

Impact of Red Wine Consumption on Cardiovascular Health Current Medicinal Chemistry, 2017, Vol. 24, No. 00 11

Author

Year

Sample Size

Treatment

Outcome

Marfella et al.

[261]

2006

RCT

115 diabetic pa-

tients with AMI

Red wine

one glass (118-ml or 4-oz

[alcohol: 11.0 g])

After 1 year, red wine administration reduced LVM

and improved the synchrony between right and left

ventricle (p<0.05 for all). These findings were associ-

ated with reduced serum level of ROS (nitrotyrosine)

and inf lammatory biomarkers (CRP. TNF-α, IL-6).

Oliveira et al.

[262]

2010

Case-control study

820 patients with

AMI vs. 2196

healthy subjects

Adherence to SEAD

Adherence to SEAD was associated with 10% reduced

the risk of AMI (OR 0.90 [95% CI 0.85-0.96]).

Levantesi et al.

GISSI-Prevenzione

Trial

[263]

2013

RCT

11,323 patients

with recent AMI

Red wine up to 0.5 and

>0.5 to ≤1 l/day.

Wine intake was associated with lower mortality risk.

Consumption up to 0.5 L/day had an adjusted HR of

0.83 (95% CI 0.74-0.92), whereas an intake >0.5 to ≤1

l/day had an HR of 0.77 (95% CI 0.63-0.94). As com-

pared with non-drinkers, the p-value for trend was

<0.01.

Cosmi et al.

GISSI-Prevenzione

Trial

[264]

2013

RCT

6,973 patients

with recent AMI

Abstainers and occa-

sional drinkers, low to

moderate (1-2

glasses/day) and high (≥3

glasses/day) consump-

tion.

Moderate wine consumption was positively associated

with better NYHA class, whereas the incidence of

hospitalization and diabetes were lower.

Hernandez-

Hernandez et al.

[265]

2015

Prospective cohort

study

14,651 subjects

Conformity with the

MADP*

Better conformity with the MADP showed a trend

toward a reduction of CVD (AMI, IS CV death), espe-

cially CV death.

RCT: randomized clinical trial; CAD: coronary artery disease FMD: flow-mediated dilatation; Aix:!augmentation index; BP: blood pressure; PCI: percutaneous

coronary intervention; IPC: ischemic preconditioning; FFQ: food-frequency questionnaire; OR: odds ratio; CI: confidence interval; HDL-c: high-density lipo-

protein cholesterol; HOMA-IR: homeostasis model assessment for insulin resistance; APOA-I: apolipoprotein A-1; Lp(a): lipoprotein a; T2DM: type 2 diabetes

mellitus; MD: Mediterranean diet; AMI: acute myocardial infarction; LVM: left ventricular mass; ROS: reactive oxygen species; CRP: C-reactive protein;

TNF: tumor necrosis factor; IL: interleukin; SEAD: So uthern Euro pean Atlantic Diet; HR: hazard ratio; NYHA: New York Health Association; MADP: Medi-

terranean alcohol-drinking pattern; CVD: cardiovascular disease; IS: ischemic stroke; CV: cardiovascular.

*MADP: 0-to-9-points score used to identify the conformity to the traditional MADP. The score sum: (1) moderate total alcohol intake; (2) alcohol intake

spread out over the week; (3) preference for wine; (4) low consumption of spirits; (5) preference for red wine over other types of wines; (6) avoidance of excess

drinking occasions; (7) consuming win e prefe rably durin g meals.

waist circumference [257]. As additional finding, red

wine was also shown to improve glycemic control, as

later confirmed in other studies [258, 259].

4.3. Red Wine, Acute Myocardial Infarction and

Heart Failure

Finally, some interesting result has been observed in

secondary prevention of CV diseases (Table 2). Lower

risk of AMI was reported after moderate intake of red

wine or other alcoholic beverages, especially when as-

sociated with Mediterranean diet. A similar result was

also observed in secondary prevention of HF, assessed

by echocardiographic parameters or NYHA class, in

association with low circulating levels of pro-

inflammatory cytokines (CRP, TNF-α, IL-6). In addi-

tion, moderate red wine intake was shown to prevent

CV mortality.he concluding lines of the article may be

presented in a short section of conclusion.

CONCLUSION

Whereas heavy and binge drinking have been related

to increased mortality and morbidity, low-to-moderate

red wine consumption has shown beneficial effects on

metabolic and CV system. However, this intriguing

evidence is mainly based on epidemiological studies

and many unsolved questions remain. A first issue con-

cerns the need to better identify chemical compounds

conferring CV protection. This may explain why bene-

ficial effects of red over white wine have not been

clearly demonstrated, although white wine, which is

usually fermented without skin and seed, is missing

many of the polyphenols. Furthermore, it should con-

sider the grape type and the growing area/conditions as

a determinant of the chemical composition of wine, as

well as a potential synergistic effect with another

component of Mediterranean diet. Secondly, available

studies are frequently biased by methodological criti-

12 Current Medicinal Chemistry, 2017, Vol. 24, No. 00 Liberale et al.

cisms. Standardization of red wine consumption could

be very difficult considering different drinking pat-

terns. In addition, others behavioral factors should be

considered: smoking, unhealthy diet and lack of physi-

cal exercise are more likely to be associated with heavy

drinking as compared to abstainers or moderate drink-

ers. It is expected that future studies will focus on bio-

chemical and pharmacological properties of red wine,

also including genetic research able to identified spe-

cific ethnic-age-gender groups that might potentially

benefit from low-moderate red wine consumption.

Meanwhile, given the global burden of alcohol-related

diseases, healthcare systems should maintain a cautious

attitude toward alcohol consumption. Furthermore, phy-

sicians should screen for excessive alcohol intake and

avoid encouraging alcohol consumption in abstainers.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial

or otherwise.

ACKNOWLEDGEMENTS

FM, FD, and FC conceived the issue and the struc-

ture of the manuscript and supervised the overall work.

LL wrote paragraphs on flavonoid polyphenols. AB

wrote the part dealing with resveratrol. FC accounted

for the part dealing with ethanol and for conclusions.

This study was supported by the European Commis-

sion (FP7-INNOVATION I HEALTH-F2-2013-602114;

Athero-B-Cell: Targeting and exploiting B cell func-

tion for treatment of cardiovascular disease). This work

was supported by a Swiss National Science Foundation

Grant to Dr. F. Montecucco (#310030_152639/1).

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Red wine alleviates atherosclerosis-related inflammatory markers in healthy subjects rather than in high cardiovascular risk subjects: A systematic review and meta-analysis

Article

Full-text available

Jun 2024
MEDICINE

Background Moderate red wine (RW) consumption is associated with a low risk of cardiovascular disease (CVD). However, few studies have evaluated the effects of RW and white wine (WW) on inflammatory markers related to atherosclerosis in healthy individuals and high-risk subjects for CVD. This study aimed to assess the effect of RW on inflammatory markers in healthy individuals and high-risk subjects for CVD compared with moderate alcohol consumption. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA) was followed in this study. The PubMed, Embase, Cochrane, Web of Science, SinoMed, EbscoHost, and ScienceDirect databases were searched. The risk of bias and quality of the included trials were assessed using the Cochrane Handbook. The main results are summarized in Stata 12. Results Twelve studies were included in the meta-analysis. The results demonstrated that RW significantly decreased circulating intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor-alpha (TNF-α), lymphocyte function-associated antigen-1, and Sialyl-Lewis X expression on the surface of monocytes in healthy subjects, but not in patients with CVD. Additionally, RW significantly decreased Sialyl-Lewis X but increased clusters of differentiation 40 (CD40) expressed on the surface of T lymphocytes and significantly decreased C-C chemokine receptor type 2 (CCR2) and very late activation antigen 4 (VLA-4) expressed on the surface of monocytes. Interestingly, subgroup analysis also found that RW significantly decreased circulating interleukin-6 (IL-6) in Spain but not in other countries, and significantly increased αMβ2 (Mac-1) in the group that had an intervention duration of less than 3 weeks. Conclusions Moderate consumption of RW is more effective than WW in alleviating atherosclerosis-related inflammatory markers in healthy people rather than high-risk subjects for CVD, but this needs to be further confirmed by studies with larger sample sizes.

Health Effects of Red Wine Consumption: A Narrative Review of an Issue That Still Deserves Debate

Article

Full-text available

Apr 2023

A strong controversy persists regarding the effect of red wine (RW) consumption and health. Guidelines for the prevention of cardiovascular diseases (CVD) and cancers discourage alcohol consumption in any form, but several studies have demonstrated that low RW intake may have positive effects on CVD risk. This review evaluated randomised controlled trials (RCTs), examining the recent literature on the correlations between acute and chronic RW consumption and health. All RCTs published in English on PubMed from 1 January 2000 to 28 February 2023 were evaluated. Ninety-one RCTs were included in this review, seven of which had a duration of more than six months. We assessed the effect of RW on: (1) antioxidant status, (2) cardiovascular function, (3) coagulation pathway and platelet function, (4) endothelial function and arterial stiffness, (5) hypertension, (6) immune function and inflammation status, (7) lipid profile and homocysteine levels, (8) body composition, type 2 diabetes and glucose metabolism, and (9) gut microbiota and the gastrointestinal tract. RW consumption mostly results in improvements in antioxidant status, thrombosis and inflammation markers, lipid profile, and gut microbiota, with conflicting results on hypertension and cardiac function. Notably, beneficial effects were observed on oxidative stress, inflammation, and nephropathy markers, with a modest decrease in CVD risk in five out of seven studies that evaluated the effect of RW consumption. These studies were conducted mainly in patients with type 2 diabetes mellitus, and had a duration between six months and two years. Additional long-term RCTs are needed to confirm these benefits, and assess the potential risks associated with RW consumption.

Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots

Article

Full-text available

May 2024

The application of fertilizers and soil quality are crucial for grape fruit quality. However, the molecular data linking different fertilizer (or soil conditioner [SC]) treatments with grape fruit quality is still lacking. In this study, we investigated three soil treatments, namely inorganic fertilizer (NPK, 343.5 kg/hm² urea [N ≥ 46%]; 166.5 kg/hm² P2O5 [P2O5 ≥ 64%]; 318 kg/hm² K2O [K2O ≥ 50%]), organic fertilizer (Org, 9 t/hm² [organic matter content ≥ 35%, N + P2O5 + K2O ≥ 13%]), and SC (SC, 3 t/hm² [humic acid ≥ 38.5%; C, 56.1%; H, 3.7%; N, 1.5%; O, 38%; S, 0.6%]), on 4-year-old Cabernet Sauvignon grapevines. Compared with the NPK- and Org-treated groups, the SC significantly improved the levels of soluble solids, tannins, anthocyanins, and total phenols in the grape berries, which are important biochemical indicators that affect wine quality. Furthermore, we conducted RNA-seq analysis on the grapevine roots from each of the three treatments and used weighted gene co-expression network analysis to identify five hub genes that were associated with the biochemical indicators of the grape berries. Furthermore, we validated the expression levels of three hub genes (ERF, JP, and SF3B) and five selected genes related to anthocyanin biosynthesis (UFGT1, UFGT2, UFGT3, GST, and AT) by using quantitative reverse transcription-polymerase chain reaction. Compared to the NPK and Org treatment groups, the SC treatment resulted in a significant increase in the transcription levels of three hub genes as well as VvUFGT1, VvUFGT3, VvGST, and VvAT. These results suggest that the SC can improve grape fruit quality by altering gene transcription patterns in grapevine roots and further influence the biochemical indices of grape fruits, particularly anthocyanin content. This study reveals that the application of SC can serve as an important measure for enhancing vineyard SC and elevating grape quality.

A decision tree model of hypertension among college students in Yunnan Province, China

Article

Full-text available

Aug 2023

Purpose: Previous studies have indicated that the prevalence rate of hypertension in adolescents is high, but it has not received much attention and the influencing factors are unclear, especially in Yunnan Province, China. Materials and methods: A cluster sampling method was used to investigate 4781 freshmen in a college in Kunming, Yunnan Province from November to December. Demographic and lifestyle data were collected using questionnaires, and height, weight and blood pressure were measured. Decision tree model of hypertension in college students was established by Chi-square automatic interactive detection method. Results: Prevalence of prehypertension of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were detected in 33.9% and 32.1%, respectively. Prevalence of hypertension of SBP and DBP was detected in 1.2% and 7.2%, respectively. The hypertension and prehypertension decision tree of SBP has gender (χ2 = 728.64, p < .001) at the first level and body mass index (BMI) (boys: χ2 = 55.98, p < .001; girls: χ2 = 79.58, p < .001) at the second level. The hypertension and prehypertension decision tree of DBP has gender (χ2 = 381.83, p < .001) at the first level, BMI (boys: χ2 = 40.54, p < .001; girls: χ2 = 48.79, p < .001) at the second level, only children (χ2 = 6.43, p = .04) and red wine consumption (χ2 = 8.17, p = .017) at the third level. Conclusions: The present study suggests that gender, BMI, only children and red wine consumption were the main factors affecting hypertension in college students in southwest border areas of China.

Determination of the polyphenolic content and the antioxidant activities of four indigenous Greek red and white wine varieties

Article

Oct 2023

Wine Polyphenol Content during the Fermentation of Vitis vinifera CS Grapes and Its Relationship with the Presence of Minerals in the Resulting Wine

Article

Full-text available

Jul 2023

The content of minerals and bioactive compounds in wine depends on various factors, among which are the origin of the grapes, their phenolic composition, and the winemaking process. This study monitored the physicochemical parameters, phenolic compound contents, and antioxidant capacity of the red grape Vitis vinifera L. “Cabernet Sauvignon” harvested in three Mexican vineyards during the first nine days of the fermentation process. The bioactive compounds and elemental composition (determined by inductively coupled plasma–optical emission spectrometry, ICP-OES) were correlated. The fermentation process decreased from 22 to 5 °Bx in all cases, while the acidity increased from 6.5 to 8 g of tartaric acid/L, decreasing the pH. The phenolic compounds extracted during the winemaking ranged from 1400 to 1600 gallic acid equivalent/L, while the antioxidant capacity was 9 mmol Trolox equivalent. The bioactive compounds identified by HPLC were resveratrol, piceid, catechin, and epicatechin. The presence of Na, Mg, and Fe was correlated with antioxidant capacity, while higher Mn, Pb, Zn, and Cu contents were related to the presence of resveratrol, piceid, and catechin in Cabernet Sauvignon wine. Thus, certain minerals present in the soil that were transferred to the V. vinifera grapes can influence the amount and type of bioactive compounds present in the wine. The phenolic content and, therefore, the organoleptic characteristics of the wine are related to the mineral composition of the vine-growing soil (origin).

Effect of fermentation technologies on the structural composition of polymeric polyphenols in aged red wines

Article

Oct 2023
J FOOD COMPOS ANAL

SIRT1 is a regulator of autophagy: Implications for the progression and treatment of myocardial ischemia-reperfusion

Article

Oct 2023
PHARMACOL RES

Overview and prospect of NAFLD: Significant roles of nutrients and dietary patterns in its progression or prevention

Article

Full-text available

Sep 2023

NAFLD is the most common chronic liver disease worldwide, characterized by lipid accumulation in the liver, and usually evolves from steatohepatitis to fibrosis, cirrhosis, or even HCC. Its incidence is rapidly rising in parallel with the increasing prevalence of obesity and metabolic syndrome. Current therapies are limited to lifestyle changes including dietary intervention and exercise, in which dietary modification exerts an important part in losing weight and preventing NAFLD. In this review, we briefly discuss the roles and mechanisms of dietary components including fructose, non-nutritive sweeteners, fat, proteins, and vitamins in the progression or prevention of NAFLD. We also summarize several popular dietary patterns such as calorie-restricted diets, intermittent fasting, ketogenic diets, Mediterranean diets, and dietary approach to stop hypertension diets and compare the effects of low-fat and low-carbohydrate diets in preventing the development of NAFLD. Moreover, we summarize the potential drugs targeting metabolic-related targets in NAFLD.

The power of berries against cardiovascular diseases

Article

Sep 2023

Cardiovascular diseases (CVDs) pose a serious threat to human health and incidence is increasing gradually. Nutrition has an important impact on the prophylaxis and progression of CVD. In this article, general attention is drawn to the possible positive effects of berries on CVD. Polyphenols have beneficial effects on the vascular system by inhibiting low-density lipoprotein oxidation and platelet aggregation, lowering blood pressure, improving endothelial dysfunction, and attenuating antioxidant defense and inflammatory responses. This review provides an overview of the effects of berries for the prevention and treatment of CVDs. Berries contain several cardioprotective antioxidants, vitamins, and numerous phytochemicals, such as phenolic compounds, that have antioxidant properties and antiplatelet activity. Phytochemical compounds in their structures can modulate dissimilar signaling pathways related to cell survival, differentiation, and growth. Important health benefits of berries include their antioxidant roles and anti-inflammatory impacts on vascular function. The effectiveness and potential of polyphenols primarily depend on the amount of bioavailability and intake. Although circulating berry metabolites can improve vascular function, their biological activities, mechanisms of action, and in vivo interactions are still unknown. Analyzing human studies or experimental studies to evaluate the bioactivity of metabolites individually and together is essential to understanding the mechanisms by which these metabolites affect vascular function.

Adiponectin signaling and function in insulin target tissues

Article

Full-text available

Mar 2016

Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide, posing a major threat on human health, productivity, and quality of life. Despite great progress made towards a better understanding of the molecular basis of diabetes, the available clinical counter-measures against insulin resistance, a defect that is central to obesity-linked type 2 diabetes, remain inadequate. Adiponectin, an abundant adipocyte-secreted factor with a wide-range of biological activities, improves insulin sensitivity in major insulin target tissues, modulates inflammatory responses, and plays a crucial role in the regulation of energy metabolism. However, adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention, and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation, and reveal therapeutic targets. Here, we discuss tissue- and cell-specific functions of adiponectin, with an emphasis on the regulation of adiponectin signaling pathways, and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation. Understanding better just why and how adiponectin and its downstream effector molecules work will be essential, together with empirical trials, to guide us to therapies that target the root cause(s) of type 2 diabetes and insulin resistance.

Clinical Evaluation of Effects of Chronic Resveratrol Supplementation on Cerebrovascular Function, Cognition, Mood, Physical Function and General Well-Being in Postmenopausal Women—Rationale and Study Design

Article

Full-text available

Mar 2016

Background: This methodological paper presents both a scientific rationale and a methodological approach for investigating the effects of resveratrol supplementation on mood and cognitive performance in postmenopausal women. Postmenopausal women have an increased risk of cognitive decline and dementia, which may be at least partly due to loss of beneficial effects of estrogen on the cerebrovasculature. We hypothesise that resveratrol, a phytoestrogen, may counteract this risk by enhancing cerebrovascular function and improving regional blood flow in response to cognitive demands. A clinical trial was designed to test this hypothesis. Method: Healthy postmenopausal women were recruited to participate in a randomised, double-blind, placebo-controlled (parallel comparison) dietary intervention trial to evaluate the effects of resveratrol supplementation (75 mg twice daily) on cognition, cerebrovascular responsiveness to cognitive tasks and overall well-being. They performed the following tests at baseline and after 14 weeks of supplementation: Rey Auditory Verbal Learning Test, Cambridge Semantic Memory Battery, the Double Span and the Trail Making Task. Cerebrovascular function was assessed simultaneously by monitoring blood flow velocity in the middle cerebral arteries using transcranial Doppler ultrasound. Conclusion: This trial provides a model approach to demonstrate that, by optimising circulatory function in the brain, resveratrol and other vasoactive nutrients may enhance mood and cognition and ameliorate the risk of developing dementia in postmenopausal women and other at-risk populations.

Mediterranean Alcohol-Drinking Pattern and the Incidence of Cardiovascular Disease and Cardiovascular Mortality: The SUN Project

Article

Full-text available

Nov 2015

Background: We assessed the still unclear effect of the overall alcohol-drinking pattern, beyond the amount of alcohol consumed, on the incidence of cardiovascular clinical disease (CVD). Methods: We followed 14,651 participants during up to 14 years. We built a score assessing simultaneously seven dimensions of alcohol consumption to capture the conformity to a traditional Mediterranean alcohol-drinking pattern (MADP). It positively scored moderate alcohol intake, alcohol intake spread out over the week, low spirit consumption, preference for wine, red wine consumption, wine consumed during meals and avoidance of binge drinking. Results: During 142,177 person-years of follow-up, 127 incident cases of CVD (myocardial infarction, stroke or cardiovascular mortality) were identified. Compared with the category of better conformity with the MADP, the low-adherence group exhibited a non-significantly higher risk (HR) of total CVD ((95% CI) = 1.55 (0.58-4.16)). This direct association with a departure from the traditional MADP was even stronger for cardiovascular mortality (HR (95% CI) = 3.35 (0.77-14.5)). Nevertheless, all these associations were statistically non-significant. Conclusion: Better conformity with the MADP seemed to be associated with lower cardiovascular risk in most point estimates; however, no significant results were found and more powered studies are needed to clarify the role of the MADP on CVD.

Nitric oxide production and endothelium-dependent vasorelaxation induced by wine polyphenols in rat aorta.

Article

Mar 1997

Association of alcohol consumption with selected cardiovascular disease outcomes: A systematic review and meta-analysis

Article

Jan 2011

Cellular recruitment in myocardial ischemia/reperfusion injury

Article

Apr 2016
EUR J CLIN INVEST

Background: Myocardial infarction is strictly linked to atherosclerosis. Beyond the mechanical narrowing of coronary vessels lumen, during MI a great burden of inflammation is carried out. One of the crucial events is represented by the ischemia/reperfusion injury, a complex event involving inflammatory cells (such as neutrophils, platelets, monocytes/macrophages, lymphocytes, and mast cells) and key activating signals (such as cytokines, chemokines, and growth factors). Cardiac repair following myocardial infarction is dependent on a finely regulated response involving sequential recruitment and clearance of different subsets of inflammatory cells. Materials and methods: This narrative review was based on the works detected on PubMed and MEDLINE up to November 2015. Results: Infarct healing classically follows three overlapping phases: the inflammatory phase, in which the innate immune pathways are activated and inflammatory leukocytes are recruited in order to clear the wound from dead cells; the proliferative phase, characterized by the suppression of pro-inflammatory signaling and infiltration of "repairing" cells secreting matrix proteins in the injured area; and the maturation phase, that is associated with quiescence and elimination of the reparative cells together with cross-linking of the matrix. All these phases are timely regulated by production soluble mediators, such as cytokines, chemokines, and growth factors. Conclusion: Targeting inflammatory cell recruitment early during reperfusion and healing might be promising to selectively abrogate injury and favoring repair. This approach might substantially improve adverse post-ischemic left ventricle remodeling, characterized by dilation, hypertrophy of viable segments, and progressive dysfunction. This article is protected by copyright. All rights reserved.

Resveratrol Provides Neuroprotection by Inhibiting Phosphodiesterases and Regulating the cAMP/AMPK/SIRT1 Pathway after Stroke in Rats

Article

Feb 2016

Dysfunction of energy metabolism can be a significant and fundamental pathophysiological basis for strokes. In studies of both humans and rodents, resveratrol, a natural polyphenol, has been reported to provide protection from cerebral ischemic injury by regulating expression of silent mating type information regulation 2 homolog 1 (SIRT1). However, direct evidence demonstrating that resveratrol exerts neuroprotection from cerebral ischemia injury by decreasing energy consumption is still lacking. Therefore, the aim of this study was to elucidate the mechanisms and signaling pathways through which resveratrol regulates energy metabolism in the ischemic brain, and to identify potential targets of resveratrol. ATP levels in brain tissues were detected by high performance liquid chromatography. SIRT1 and the phosphorylation of adenosine-monophosphate-activated protein kinase (P-AMPK) expressiones were evaluated by western blot. Levels of phosphodiesterase (PDEs) and cAMP were quantitated by real-time PCR and ELISA, respectively. Results showed that resveratrol significantly reduced the harmful effects of cerebral ischemic injury in vivo. Moreover, levels of ATP, p-AMPK, SIRT1, and cAMP were increased by resveratrol and PDE inhibitors. In conclusion, our findings indicate that resveratrol provides neuroprotection by inhibiting PDEs and regulating the cAMP/AMPK/SIRT1 pathway, which reduces ATP energy consumption during ischemia.

Long-term inhibition of rhokinase ameliorates hypoxia-induced pulmonary hypertension in mice independent of endothelial NO synthase

Article

Jan 2003
CIRCULATION

Pathophysiology of ST-segment elevation myocardial infarction: Novel mechanisms and treatments

Article

Nov 2015
EUR HEART J

Despite major advances in mechanical and pharmacological reperfusion strategies to improve acute myocardial infarction (MI) injury, substantial mortality, morbidity, and socioeconomic burden still exists. To further reduce infarct size and thus ameliorate clinical outcome, the focus has also shifted towards early detection of MI with high-sensitive troponin assays, imaging, cardioprotection against pathophysiological targets of myocardial reperfusion injury with mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and hypoxemia) and newer pharmacological interventions (atrial natriuretic peptide, cyclosporine A, and exenatide). Evidence from animal models of myocardial ischaemia and reperfusion also demonstrated promising results on more selective anti-inflammatory compounds that require additional validation in humans. Cardiac stem cell treatment also hold promise to reduce infarct size and negative remodelling of the left ventricle that may further improves symptoms and prognosis in these patients. This review focuses on the pathophysiology, detection, and reperfusion strategies of ST-segment elevation MI as well as current and future challenges to reduce ischaemia/reperfusion injury and infarct size that may result in a further improved outcome in these patients.

Resveratrol improves delayed r-tPA treatment outcome by reducing MMPs

Article

Oct 2015
ACTA NEUROL SCAND

Objectives: Although recombinant tissue plasminogen activator (r-tPA) is currently the most effective treatment for brain ischemic stroke, the 3-h narrow therapeutic windows severely limits its clinical efficacy. We aim to investigate the effect of resveratrol on improving treatment outcomes of delayed r-tPA administration. Materials & methods: Patients were randomly divided according to their onset-to-treatment time (OTT), as early OTT or delayed OTT. Then, they were either treated with r-tPA + placebo or with r-tPA + resveratrol. Twenty-four hours after the treatment, outcomes were assessed with NIH stroke scale (NIHSS), and plasma levels of MMP-2 and MMP-9 were also examined with ELISA. Results: In patients receiving delayed r-tPA treatment, co-administration of resveratrol significantly improves their treatment outcomes compared with those receiving placebo, as indicated by improved NIHSS scores. This improved outcome was be caused by resveratrol-induced reduction in plasma levels of both matrix metalloproteinase (MMP)-2 and MMP-9, as a positive correlation was observed between reductions in both MMPs and patient NIHSS scores. Conclusions: Resveratrol could be potentially administered as an adjuvant with r-tPA treatment, which extends the clinical therapeutic window of r-tPA, therefore improving the outcome of patients receiving late stroke treatment.

Impact of Red Wine Consumption on Cardiovascular Health

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