574 A. D ́avalos and M. A. Lasunci ́on
have been shown to increase plasma/serum antioxidant activity and to protect LDL
from oxidation evaluated both by the ex vivo susceptibility of the LDL particles to
oxidation induced by Cu^2 +or other oxidant agents and by analysis of oxidized LDL
in plasma/serum (Avellone et al. 2006; Covas et al. 2003; di Bari et al. 2003; Frankel
et al. 1993; Castilla et al. 2006). Consequently, the potent antioxidant activity of
phenolic compounds in red wine has been proposed as an explanation for the French
paradox (de Whalley et al. 1990). In vivo inhibition of LDL oxidation is only a minor
part of the real complex effect exhibited by polyphenols in different processes. The
recent in vivo demonstration that polyphenols from supplementation, in this case
tea polyphenols, effectively reach tissuecells (Henning et al. 2006) provides new
insight into the effect of wine polyphenols and polyphenols from other sources,
complementing the extensive data on their effects at the cellular level, evaluated to
date only in in vitro models. Free radical quenching is only a simplistic explanation
of how polyphenols could exert their effects. The action of polyphenols on different
pathways is complex and is still not well understood.
The mitogen-activated protein kinases (MAPKs) are a family of serine/threonine
kinases that play an important role in the transduction of signals that coordinate
the cellular response to different cellular environmental stimuli. The pathway ulti-
mately modulates gene transcription in the nucleus and mediates various physio-
logical and pathological changes in cell function (Roux and Blenis 2004; Huang
et al. 2004). JNK/SAPK, p38, and ERK are the major proteins in the MAPK
family. Several approaches have been used to evaluate the role of MAPKs in modu-
lating the beneficial effects of polyphenols. Atherosclerosis progression is character-
ized by endothelial dysfunction. Independently of their antioxidant activity, which
may increase the bioavailability of nitric oxide (NO), wine polyphenols improve
endothelial function both via an increased expression of endothelial nitric oxide syn-
thase (eNOS) (Leikert et al. 2002; Wallerath et al. 2002) and an activation of eNOS
that is dependent upon the activation of phosphatidylinositol 3-kinase (PI3K)-Akt
pathway through the activation of p38MAPK alpha, resulting in an increased forma-
tion of NO (Anter et al. 2004; Ndiaye et al. 2005; Stoclet et al. 2004). Synthesis of
endothelin-1, an endothelium-derived peptide with potent vasoconstrictor and pro-
liferative properties, have also been reported to be inhibited by wine procyanidins
(Corder et al., 2001, 2006). The mechanism involved in this effect has yet to be
fully elucidated; however, interfering with the ERK1/2 pathway through attenuation
of ROS formation may be involved (Liu et al. 2003).
Advanced plaque formation is accelerated by formation of new blood ves-
sels, proliferation and migration of vascular smooth muscle cells (VSMCs), and
increased degradation of extracellular matrix predominantly by matrix metallo-
proteinases (MMP). Red wine polyphenols inhibit VSMC migration induced by
platelet-derived grow factor via inhibition of PI3K activity and the p38 MAPK
pathway; this effect is mediated by inhibition of phosphorylation of MKK3/6, a
kinase upstream of p38MAPK (Iijima et al.2002). Expression of major proangio-
genic factors, vascular endothelial growth factor (VEGF), and MMP-2 has been
shown to be reduced by wine polyphenols (Baron-Menguy et al. 2007; El Bedoui
et al. 2005; Oak et al. 2003, 2004). VEGF expression was inhibited by preventing