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Review
Abstract
Keywords: Red wine polyphenols; Atherosclerosis; Endothelial function; Signal transduction; Vasodilation
1. Introduction
For many numbers of years, considerable attention has
been directed towards human behavioural habits that could
either be considered risk factors or even protective elements
for developing chronic pathologies. In particular, much effort
has been devoted to elucidate the role of diet in preventing
cardiovascular diseases. A so-called Mediterranean diet is
thought to prevent cardiovascular diseases [1], as a consequence of its high content of antioxidants, which are crucial in
ameliorating oxidative events implicated in many diseases.
Similarly, moderate consumption of red wine has been
associated with a lowering of the risk of coronary heart
disease [2 4]. Red wine represents a rich source of polyphenols such as anthocyanosides (ACs), catechins, proanthocyanidins (PAs), stilbenes and other phenolics. Anthocyanosides (ACs) are flavonoids widely distributed in fruits
and vegetables. They provide colour to red wines and to skins
of red and black grapes [5]. Proanthocyanidins are another
class of plant phenol metabolites widely occurring in fruits
* Corresponding author. Tel.: +39-02-50318345; fax: +39-02-50318391.
E-mail address: mario.dellagli@unimi.it (M. DellAgli).
including grapes [6]. ACs and PAs are among the most
important compounds in determining the quality of the red
wine, because they greatly influence colour, bitterness, astringency, and chemical stability toward oxidation [7].
In addition to antioxidant/antiradical activity, red wine
polyphenols (RWPs) were shown to possess many biological
properties including the inhibition of platelet aggregation,
vasorelaxing activity, modulation of lipid metabolism, and
inhibition of low-density lipoprotein oxidation [2,3,8 11].
Thus, the health benefits of moderate consumption of red
wine are founded on a multiplicity of actions. The biological
properties of red wine stilbenes (trans-resveratrol) have been
extensively reviewed [12 14]. Because ACs and PAs exert
cardioprotective effects which are not only due to antioxidant/
antiradical activity, the present review will consider the
effects of ACs and PAs at vascular level with special emphasis
on the vasorelaxing and the antiaggregating properties.
2. Proanthocyanidins and anthocyanosides in red grapes
(Vitis vinifera) and wines
PAs (or so-called condensed tannins) are high-molecular
weight polymers, made of flavan-3-ol units (Fig. 1) linked
0008-6363/$ - see front matter D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2004.03.019
Moderate consumption of red wine has been putatively associated with lowering the risk of developing coronary heart disease. This
beneficial effect is mainly attributed to the occurrence of polyphenol compounds such as anthocyanosides (ACs), catechins,
proanthocyanidins (PAs), stilbenes and other phenolics in red wine. This review focuses on the vascular effects of red wine polyphenols
(RWPs), with emphasis on anthocyanosides and proanthocyanidins. From in vitro studies, the effect of red wine polyphenols on the vascular
tone is thought to be due to short- and long-term mechanisms. NO-mediated vasorelaxation represents the short-term response to wine
polyphenols, which exert the effect by increasing the influx of extracellular Ca2 +, and the mobilization of intracellular Ca2 + in endothelial
cells. Polyphenolic compounds may also have long-term properties, as they increase endothelial NO synthase expression acting on the
promoter activity. In addition, they decrease the expression of adhesion molecules and growth factors, involved in migration and proliferation
of vascular smooth muscle cells. Moreover, they inhibit platelet aggregation. However, a paucity of data as regards the bioavailability and
metabolism of these compounds in human studies is a limiting factor to proving their efficacy in vivo.
D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
594
595
Dysfunction of the vascular endothelial cells, and proliferation and migration of smooth muscle cells are among the
factors contributing to atherosclerosis. Vascular endothelium
synthesises and releases nitric oxide (NO), which in turns,
promotes vasorelaxation (endothelium-dependent), reduces
platelet aggregation, and limits the flux of atherogenic
plasma proteins into the artery wall (Fig. 5). The vasorelaxant effect of NO occurs through the activation of
guanyl cyclase leading to the accumulation of cGMP [22].
The interaction between wine polyphenols and cell metabolism in the vascular tissue has been extensively investigated. These studies aimed to support for the beneficial effects
of wine consumption in preventing cardiovascular diseases.
In several animal models, the administration of red wine,
grape juice, dealcoholized red wine and PAs extract from
grape seeds attenuated the development of atherosclerotic
lesions [23 26]. In a pig model, the consumption of RWPs
induced a partial reduction of thickness of intimal proliferation even if not statistically significant [27]. Several
processes of vascular reactivity seem to be influenced by
wine ingredients. Red wine supplementation modulated
haemostatic function and prevented thrombosis in experimental animals [10,28,29]. Wine polyphenols were shown
to modulate blood pressure, promote vasodilatation, inhibit
smooth muscle cell migration and proliferation, and inhibit
platelet aggregation.
596
intracellular stores. The authors suggested that Ca2 + signalling pathways leading to NO production could involve the
activation of multiple cellular targets (G-proteins, phospholipase C, tyrosine kinase), depending on the composition of
the polyphenol mixture. In addition to increased NO synthase activity, RWPs may prolong the half-life and increase
the bioavailability of NO, by reducing its degradation
mediated by reactive oxygen species [27].
3.2. Modulation of gene expression by red wine polyphenols
All events previously described are responsible for a
short-term response mediated by RWPs. Recent studies
pointed out that polyphenolic compounds from several
sources may also have long-term properties, as they are
able to modulate gene expression in different cancer cell
lines and in macrophages [48 50].
RWPs significantly increased NO synthase expression,
acting on the promoter activity [51]. Thus, polyphenols not
only activate the enzyme, but also increase its levels, which
might lead to a long-lasting effect. Adhesion of leukocytes,
monocytes and T-lymphocytes to the vascular endothelium
is among the earliest events in inflammatory response and
atherogenesis. Successively, accumulation of leukocytes in
the arterial intima can make atherosclerotic plaque worsening. Adhesion process is facilitated by the action of endothelial-leucocyte adhesion molecules, which include
intercellular adhesion molecule 1 (ICAM-1), E-selectin
and vascular cell adhesion molecule 1 (VCAM-1). The
expression of these molecules can be transcriptionally
regulated by inflammatory cytokines such as interleukin-1
alpha and tumor necrosis factor alpha (TNF-a). It was
reported that at 5 Ag/ml, PAs extracted from grape seeds
downregulated the TNF-a induced expression of VCAM-1
Vascular smooth muscle cells contribute to the pathogenesis of atherosclerotic lesions, in as much as their
proliferation and migration are critical events for progressive intimal thickening and development of arterial wall
sclerosis. At the site of the lesion formation, the most potent
mitogenic and chemotactic agent for vascular smooth muscle cells is platelet-derived growth factor (PDGF) released
by platelets, endothelial cells and vascular smooth muscle
cells themselves. PDGF exerts its biological effects via
activation of two subtypes of transmembrane receptor
tyrosine kinases, termed a and h PDGF receptor. Ligand
binding to the h receptor promotes the activation of signalling enzymes which are important for cell migration and
proliferation. Activation of phosphatidylinositol 3V-kinase
(PI3K) and mitogen-activated protein kinase (MAPK) pathways as response to PDGF is implicated in vascular smooth
muscle cells motility [56 58].
Then, the effect of RWPs on the proliferation and the
migration of cultured vascular smooth muscle cells has also
been investigated [59,60]. RWPs (1 100 Ag/ml) inhibited
rat aortic smooth muscle cells proliferation and DNA
synthesis. Polyphenol fractions of different molecular
weights, c 200 400 for monomeric components (ACs,
catechins and flavonoids) and 1600 2000 for oligomeric
PAs, showed similar antiproliferative effects. Two distinct
mechanisms have been postulated. One involves the downregulation of cyclin A gene expression, through the decreased expression of transcription factors ATF-1 and CREB
(cAMP-responsive element). The second is associated with
the downregulation of PI3K activity, which is known to
interfere with cell-cycle regulation via the upregulation of
p27kip1 acting as inhibitor of cyclin-dependent kinase
[61,62]. In addition to proliferation, RWPs (1 100 Ag/ml)
inhibited vascular smooth muscle cell migration through the
specific inhibition of PI3K and p38MAPK, but not through
other MAPKs and ERK 1/2 (extracellular signal-regulated
597
598
Acknowledgements
This review is dedicated to the memory of Professor
Giovanni Galli. We gratefully acknowledge Dr. Germana
Galli for her help during the preparation of this manuscript.
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