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Flavonoids and Cardiovascular Disease

Myron Gross

To cite this article: Myron Gross (2004) Flavonoids and Cardiovascular Disease, Pharmaceutical
Biology, 42:sup1, 21-35, DOI: 10.3109/13880200490893483

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Pharmaceutical Biology
2004, Vol. 42, Supplement, pp. 21–35
Flavonoids and Cardiovascular Disease
Myron Gross
Molecular Epidemiology and Biomarker Research Laboratory, Department of Laboratory Medicine and Pathology,
School of Medicine, Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis,
Minnesota, USA
Abstract
Diets high in flavonoids have long been associated with
nutritional recommendations, a healthy lifestyle, and
the prevention of chronic diseases. However, identifi-
cation of specific beneficial effects from specific flavo-
noids and flavonoid-rich foods has been a challenging
area, probably due to a nonessential or conditional role
for flavonoids in human nutrition. Nonetheless, recent
efforts in the area of high flavonoid–containing foods
and cardiovascular disease have begun providing the first
demonstrations of specific effects and mechanisms of
action in well-controlled studies. The early studies have
shown that flavonoids have several anti-atherosclerotic
activities including anti-inflammatory, antioxidant, anti-
proliferative, antiplatelet, and provessel function activi-
ties. Cholesterol-lowering and antihypertensive effects
of flavonoids have been studied and appear minimal in
humans. The studies also demonstrate several possible
mechanisms and pleiotropic effects of flavonoids that
may be active in reduction in the risk of cardiovascular
disease. Several subclasses of flavonoids may contribute
toward the apparent beneficial effects and include fla-
vones, flavonols, flavanones, catechins isoflavones,
proanthocyanidins, and anthocyanidins. Further studies
are necessary for confirmation of the beneficial effects,
identification of dose-response relationships, and identi-
fication the most bioactive flavonoids.
Keywords: Anti-inflammation, antioxidant, atheroscler-
osis, bioactivity, cardiovascular disease, cell prolifer-
ation, flavonoids, platelets, vessel function.
Introduction
In recent years, flavonoids have been recognized as
compounds with potent biological activities that may
Accepted: September 15, 2004
Address correspondence to: Myron Gross, Ph.D., Department of Laboratory Medicine and Pathology, University of Minnesota, MMC
609, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA. Tel.: (612) 624-5417; Fax: (612) 273-6994.
DOI: 10.1080/13880200490893483
be active in the prevention of chronic diseases including
cardiovascular disease. Significant dietary intakes of fla-
vonoids occur with fruit and vegetable intakes, especially
apples, onions, and certain beverages including tea and
cocoa. Their antioxidant activity is well established,
and epidemiologic studies have suggested associations
between flavonoid intake and a lower risk of cardio-
vascular disease. Flavonoids may prevent oxidative
damage and the oxidation of low-density lipoproteins
(LDL), but importantly, several additional possible
activities have been studied in cellular, experimental
animal, and human experiments. Flavonoids may have
anti-inflammatory, cholesterol-lowering, antihyperten-
sive and antiplatelet activities. These compounds also
may inhibit smooth muscle cell proliferation and
migration and improve vessel function. Recent findings
in each of these major areas of biological activity are
reviewed herein, and further research needs are iden-
tified. The studies described herein include those evaluat-
ing the effects of flavonoids from all major subclasses
(Fig. 1) with the exception of isoflavones, which have
been the subject of several recent reviews (Knight &
Eden, 1996; Anthony et al., 1998; St Clair, 1998; Tham
et al., 1998; Setchell & Cassidy, 1999; Lissin & Cooke,
2000), and the compounds that may be classified as
proanthocyanidins, which are described in Chapter 1 of
this issue. Thus, the effects of the following major
subclasses of flavonoids are described herein: flavones,
flavonols, flavanones, catechins, and anthocyanidins.
Anti-inflammatory activities
A major hypothesis focuses on inflammation as a funda-
mental cause in the pathogenesis of coronary heart
# 2004 Taylor & Francis Ltd.
22
Figure 1. The major subclasses of flavonoids. Classification is based on variations in the heterocyclic C-ring.
disease. The inflammatory response encompasses a wide
range of activities including an increase in oxidative
stress, an increase in capillary permeability, accumu-
lation of white blood cells, release of cytokines (interleu-
kins, TNF), induction of various enzyme activities
(oxygenases, nitric oxide synthetase, peroxidases), and
induction of arachidonic acid metabolism and cellular
adhesion molecules, such as intercellular adhesion mol-
ecule (ICAM) and vascular cell adhesion molecule
(VCAM). These activities may be diminished by flavo-
noids, which have a wide range of anti-inflammatory
activities. The anti-inflammatory activities of flavonoids
have been demonstrated in numerous cellular and animal
models; however, human studies generally are lacking in
this area. The various anti-inflammatory activities of
flavonoids and some limitations of research in this area
are described herein.
The most commonly occurring flavonoid, quercetin,
and its conjugate, rutin, has demonstrated significant
anti-inflammatory activity in several systems, including
the rat paw system and neutrophils. In these systems,
rutin suppresses the inflammatory reaction, most obvi-
ously indicated by a reduction in edema and a reduction
in the chemotaxis of neutrophils (Selloum et al., 2003).
Intraperitoneal administration of rutin and quercetin
reduce both acute and chronic inflammation in a rat
model (Guardia et al., 2001). Lipopolysaccaride (LPS)-
induced inflammatory reactions are associated with an
elevated level of NO release, which may lead to an
increase in oxidative stress. Quercetin, rutin, and wogo-
nin inhibit this release through suppression of inducible
NOS (nitric oxide synthase) expression (Shen et al.,
2002). They also suppress cyclooxygenase-2 (COX-2)
gene expression and prostaglandin E2 formation
(Chen et al., 2001). Thus, these flavonols have potent
M. Gross
anti-inflammatory activities that influence several
inflammatory responses.
Specific types of oxidative stress are associated with
inflammatory responses and may be reduced by flavo-
noids. Inflammation produces hypochlorous acid, a
strong oxidant, via myeloperoxidase activity. The com-
mon dietary flavonols quercetin and rutin become
chlorinated in the presence of HOCl and may prevent
the oxidative damage associated with exposure to
HOCl (Binsack et al., 2001). An overproduction of
nitric oxide has been associated with inflammatory
responses. The flavones apigenin and luteolin are
potent inhibitors of nitric oxide formation by activated
macrophages (Scuro et al., 2004), a major cellular
component involved in atherosclerosis. These specific
examples illustrate the types of antioxidant activity
that various flavonoids may have in the prevention of
oxidative damage associated with inflammatory
responses.
Specific anti-inflammatory activities of individual
flavonoids include the following. Nobiletin has shown a
number of anti-inflammatory activities in cell systems.
These include suppression of cyclooxygenases, prosta-
glandin E2, and several proinflammatory cytokines includ-
ing interleukin (IL)-1a, IL-1b, tumor necrosis factor
(TNF)-a, and IL-6 (Lin et al., 2003). In addition, nobelitin
suppresses the production of promatrix metalloproteinase
(Ishiwa et al., 2000; Sato et al., 2002), a factor associated
with vascular plaque stability. Luteolin is identified as
the active anti-inflammatory factor in Perilla frutescens
(L.) Briton var. acuta kydoformaviridis makino. In a
mouse model, it inhibits TNF-a activity, arachidonic
acid–induced and 12-O-Tetradecanoylphorbol-13-acetate
(TPA)-induced ear edema, and oxazolone-induced allergic
edema (Ueda et al., 2002). The expression of TNF-a and
 Flavonoids and cardiovascular disease
intercellular adhesion molecule-1 (ICAM-1) in lipopolysac-
caride-treated mice is reduced by luteolin treatment. The
treatment also reduces lung and liver infiltration by leuko-
cytes (Kotanidou et al., 2002). Similar results also were
found in an earlier study (Xagorari et al., 2001). Luteolin
effectively inhibited asthmatic responses in several studies
(Park et al., 1999; Kimata et al., 2000a, 2000b), and path-
ways for this inhibitory activity have been identified
(Xagorari et al., 2001, 2002). Cadmium-induced inflam-
mation is diminished by tea catechins (Choi et al., 2002).
The activities of several inflammatory factors are dimin-
ished and include phospholipase A2, platelet cyclooxy-
genase, platelet thromboxane A2, 50 -lipooxygenase, and
leukotriene B4. The thrombocyte synthesis index, the pros-
taglandin (PG) I2=thromboxane A2 ratio, is increased by
tea catechins. Myricetinglucuronide has anti-inflammatory
activity in the rat paw model of inflammation (Hiermann
et al., 1998). Its activity may involve inhibition of COX-1,
COX-2, and 50 -lipooxygenase (5-LOX).
Blackberry extracts contain anthocyanins, primarily
cyanidin-3-O-glucoside, which may have anti-inflamma-
tory activity. In a lung acute inflammation model (carra-
geenan-induced acute inflammation), the blackberry
extracts reduce fluid accumulation, neutrophil accumu-
lation, polymorphonuclear leukocyte accumulation, and
lipid peroxidation. Nitrite=nitrate (products of NO
production) and prostaglandin E2 levels also are reduced
by the extract (Rossi et al., 2003). Purified anthocyan-
dins, malvidin and cyanidin, and galloyl derivatives of
catechins have shown COX inhibitory activities (Seeram
et al., 2003). Thus, anthocyanins in blackberry extracts
are active agents and have anti-inflammatory activities.
The blackberry extract may affect several pathways,
and its multifaceted actions may be the basis for its
potent inhibitory activity. Importantly, the anthocyanin
effect may be unique. Anthocyanins induce TNF-a
production in a cellular system, RAW264.7 macro-
phages, which are activated by LPS=interferon-c. This
is in contrast to several other flavonoids that inhibit
TNF-a production. Thus, anti-inflammatory effects of
anthocyanins may use mechanisms that differ from those
of other flavonoids.
Mediterranean diets have a high content of flavo-
noids, in particular, resveratrol. Resveratrol inhibited
expression of the vascular cell adhesion molecule-1
(VCAM-1) in response to bacterial LPS (Carluccio et al.,
2003). The activities of resveratrol and other flavonoids
in the Mediterranean diet suggest that this diet may have
an anti-inflammatory effect.
Antibacterial activities have been demonstrated for
quercetin, quercitrin, and morin. Moreover, synergy is
demonstrated between these flavonoids and rutin in
their antibacterial activity (Arima et al., 2002).
Flavonoids have antibacterial activities against several
antibiotic-resistant bacterial strains. Myricetin, datisce-
tin, kaempferol, quercetin, flavone, and luteolin inhibit
23
methicillin-resistant Staphylococcus aureus Myricetin
may have a broad spectrum of. activity as it inhibits
several additional antibiotic-resistant organisms (Xu &
Lee, 2001). Thus, flavonoids may be active in the
reduction of bacteria infections and the associated
inflammatory response.
In summary, several flavonoids have demonstrated
potent anti-inflammatory activities and may reduce
inflammation that results from a variety of causes
including antibiotic-resistant bacteria. These flavonoids
inhibit several key steps in inflammation and have
been used as anti-inflammatory agents in some
instances. Anti-inflammatory activity may be a
common property of flavonoids as it is found in
compounds from several flavonoid subclasses. Thus,
total flavonoid exposure may be more important than
exposures to specific flavonoid compounds for the pre-
vention of inflammation. It is possible that the anti-
inflammatory activity of flavonoids influences the
inflammation associated with atherosclerosis and is
a promising area of investigation. Several types of
information are essential for progress in this area of
investigation. In particular, human studies and dose-
response studies are lacking. It is unknown whether
typical flavonoid intakes influence the low levels of
inflammation that now have been associated with an
increased risk of coronary heart disease (Libby &
Ridker, 2004; Ridker et al., 2004; Willerson & Ridker,
2004). Also, the influence of human flavonoid
metabolism on anti-inflammatory activities remains
unknown. Fundamental studies in these areas may
provide an understanding of the role of flavonoids in
the prevention of coronary heart disease. Thus, the
influence of flavonoids on inflammation in humans
should receive additional attention and remain an
active area of investigation.
Vascular smooth muscle cells
The proliferation of vascular smooth muscle cells is a
consistent feature in the development of atherosclerotic
plaque. Apigenin is a potent inhibitor of growth
factor–induced rat aortic vascular smooth muscle cell
growth (Kim et al., 2002). A major flavonoid constituent
of tea, epigallocatechin gallate (EGCG), is a potent
inhibitor of rat aortic smooth muscle cells. This activity
is mediated by Ras=JNK and the downregulation of c-
jun (Hwang et al., 2002). Red wine polyphenols inhibit
the migration of vascular smooth muscle cells. The inhi-
bition occurs through two pathways, the PI3K activity
and p38 (MAPK) pathways (Iijima et al., 2002). Thus,
flavonoids may be a significant inhibitor of vascular
smooth muscle growth and migration. Further studies
are necessary for confirmation of the effect and evalu-
ation in additional models.
24 M. Gross
Antioxidant activity
Flavonoids are potent antioxidants that may affect initial
steps in the development of atherosclerosis through the
prevention of LDL oxidation, blockage of LDL uptake
by macrophages, and prevention of foam cell formation.
In support of these possible activities, flavonoids prevent
atherosclerosis in an animal model (Hayek et al., 1997).
Apolipoprotein E–deficient mice develop atherosclerotic
lesions that are readily measured by 10 weeks of age.
These lesions are prevented by the consumption of red
wine and catechin- and quercetin-supplemented water
for 6 weeks. Susceptibility to oxidation also was reduced
in the mice receiving red wine or the flavonoid-supple-
mented water. In addition, various flavonoids display
several antioxidant activities that are relevant to the pre-
vention of atherosclerosis. For example, the isoflavone
genistein has demonstrated antioxidant activities in cell-
free and cell-mediated systems. These include the preven-
tion of LDL oxidation and protection of vascular cells
against oxidized LDL particles (Kapiotis et al., 1997).
Nobiletin has extensive antioxidant activities. It sup-
presses the formation of oxidants by three systems
including the xanthine oxidase system, TPA-induced oxi-
dative stress, and NO (nitric oxide) generation by the
RAW264.7 cell line (Murakami et al., 2000a, 2000b).
These are just a few examples of activities that are found
in a wide range of flavonoids.
The antioxidant activity of flavonoids may occur
through several mechanisms including scavenging of
reactive oxygen=nitrogen species, chelation of metals,
inhibition of propagation reactions in lipid peroxidation,
and sparing of LDL-associated antioxidants (Fuhrman
& Aviram, 2001; Mira et al., 2002). Their antioxidant
activity also may occur through the inhibition of cellular
oxygenases and the enhancement of cellular antioxi-
dants. Detailed studies have identified structural require-
ments for the antioxidant activity of flavonoids. These
involve primarily the 4-oxo group of the C-ring,
Figure 2. Basic structure and position numbers of flavonoids.
hydroxyl groups at positions 5 and 30 , 40 and 50 , and
the double bond between positions 2 and 3 of flavonoids
(see Fig. 2 for position numbers). Recent studies have
evaluated several derivatives of flavonoids and found
additional structural features that influence antioxi-
dant activity, such as an effect of alkylation at position
7 on antioxidant activity (Kessler et al., 2003). These
studies also identified possible pro-oxidant activities of
flavonoids, which appeared to be dependent on the
presence of a free hydroxyl group at position 3. Thus,
the major structural requirements and mechanisms
are known for many of the antioxidant activities of
flavonoids.
Although flavonoids clearly have antioxidant activity
from a purely chemical standpoint, a major question is
do they act as antioxidants or pro-oxidants in biological
systems and, if so, under what conditions? A description
of recent in vitro and in vivo studies of antioxidant activi-
ties is given below for specific flavonoids and flavonoid-
rich foods.
The antioxidant activity of luteolin-7-glucoside has
been investigated in an in vivo system, which involved
the use carbon tetrachloride, a well-known oxidizing
agent, and an evaluation of liver damage. Luteolin sup-
presses several indicators of liver and oxidative damage
including serum levels of glutamic pyruvic transaminase
and glutamic oxaloacetic transaminase. Liver malondial-
dehyde and 8-hydroxydeoxyguanosine levels are lower in
the luteolin-treated as compared with controls. Glu-
tathione is elevated in the luteolin-treated group com-
pared with the control group (Qiusheng et al., 2004).
Each of these results indicates that luteolin is a potent
antioxidant in vivo.
Quercetin and its derivatives can prevent oxidative
damage in a variety of systems, including those with
apparent relevance to atherosclerosis. The flavonols myr-
icetin and quercetin prevent lipid peroxidation and may
be active in the regenerations of a-tocopherol (Gordon
& Roedig-Penman, 1998; Morel et al., 1998). Synergistic
 Flavonoids and cardiovascular disease
activities of rutin, a derivative of quercetin, with the anti-
oxidants ascorbic acid and c-terpinene were found in the
inhibition of LDL oxidation (Milde et al., 2004). Radi-
olytic oxidation of apolipoprotein B in LDL particles
can be repaired by quercetin, but not rutin. Quercetin
binds effectively with LDL particles and through intra-
molecular electron transfer repairs phenoxyl radicals
(Filipe et al., 2002a, 2000b). Oxidative damage from
UV radiation and methyl viologen can be prevented by
rutin (Palmer et al., 2002). Neutrophils are significant
sources of reactive oxygen species that may be overex-
pressed in immune responses and cause tissue damage.
This response can be inhibited by two flavonoids, trihy-
droxyethylrutin and disodium flavodate (Wenisch &
Biffignandi, 2001). Rutin was an effective inhibitor of
free-radical production by monocytes and neutrophils
from rheumatoid arthritis patients (Ostrakhovitch &
Afanas’ev, 2001). Thus, quercetin or its derivatives can
inhibit oxidation in several of the major components that
are involved in atherosclerosis. In addition, antioxidant
status may be improved by the intake of quercetin or
its derivatives. The intake of rutin enhances the antioxi-
dant status of mouse liver tissue and Mn-superoxide dis-
mutase activity (Gao et al., 2002). Higher amounts
decrease catalase activity and reduce the concentration
of antioxidant minerals including iron, zinc, and copper.
These later responses of antioxidant enzymes and miner-
als may reflect a decreased need for their activity as a
result of improved antioxidant status.
Antioxidant concentrations and oxidative damage
indicators have been evaluated in a human study of rutin
supplementation. The consumption of 500 mg of rutin
per day increased plasma levels of quercetin, kaempferol,
and isorhamnetin. It did not change the levels of oxidized
lymphocyte DNA, urinary malondialdehyde, oxidized
DNA, and F2-isoprostanes. Thus, rutin remains unpro-
ven as an in vivo antioxidant. Nonetheless, an important
result was that no adverse changes were found in blood
chemistries of the subjects (Boyle et al., 2000).
The antioxidant activity of common anthocyanidins
and their aglycones has been evaluated in several lipid
environments, including LDL particles, and bulk and
emulsified methyl linoleate. The anthocyanidins are
strong antioxidants and effectively prevent oxidative
damage in these environments (Kahkonen & Heinonen,
2003). Structure-activity relationships for the antioxidant
activity have been identified for many of the commonly
consumed anthocyanidins and anthocyanins (Seeram &
Nair, 2002). Galloylation is an important determinant
of antioxidant activity in anthocyanidins (Plumb et al.,
1998).
The anthocyanins demonstrate antioxidant activity
in several cell and animal systems as well as in humans.
Anthocyanins inhibit NO formation in LPS=interferon-
c–activated RAW264.7 macrophages (Wang & Mazza,
2002), and the mechanism of antioxidant activity has
25
been described (Tsuda et al., 2000b). Anthocyanins
(elderberry extracts) protect endothelial cells against
several oxidative stressors, including hydrogen peroxide,
AAPH (2,20 -azobis(2-amidinopropane), and Fe=ascorbic
acid (Youdim et al., 2000). The anthocyanidin cyandin 3-
O-beta-D-glucoside was an effective antioxidant in the
hepatic ischemia-reperfusion rat model. It suppressed
the formation of thiobarbituric acid–reactive substances
and spared reduced glutathione (Tsuda et al., 2000a).
Acylated anthocyanins reduce oxidative stress in the rat
model of paraquat-induced oxidative damage (Igarashi
et al., 2000). Notably, anthocyanin-rich diets did not
influence cholesterol or fatty acid patterns in the livers
of rats. The rats fed black currant and elderberries did
appear to spare vitamin E. Similar results are found for
cyanidin-3-O-glucoside (Frank et al., 2002). Postprandial
oxidative stress is reduced in human subjects by the con-
sumption of a proanthocyanidin-rich grape seed extract
(Kahkonen & Heinonen, 2003; Natella et al., 2002). Con-
sumption of blueberries increased Oxygen Radical
Absorption Capacity (ORAC) activity in the blood of
human subjects (Mazza et al., 2002). These studies sug-
gest that anthocyanins act as antioxidants in biological
systems and may be active in human subjects. Their
relative importance in humans remains unknown and
requires substantial additional experimentation.
The most commonly consumed flavonoids, catechins,
are in tea. These compounds have a wide range of anti-
oxidant activities. Electron paramagnetic resonance
experiments demonstrated the quenching of singlet oxy-
gen, superoxide anion, and hydroxyl radicals by black
and green tea extracts (Thiagarajan et al., 2001). Hydro-
gen peroxide- and primaquine-induced lipid peroxidation
is prevented by prior incubation with tea polyphenols.
The tea polyphenols inhibit hydroxyl radical fluxes gen-
erated by an iron-ascorbic acid system, suggesting that
iron chelation may be a mode of polyphenol action.
Tea flavonoids inhibit macrophage- and human umbili-
cal vein endothelial cell–induced LDL oxidation
(Yoshida et al., 1999). Theaflavin digallate was the most
effective. The mechanism of action may be the chelation
of iron and decreased formation of superoxide anion.
Green tea catechins also were effective in the prevention
of cell-mediated LDL oxidation (Yang & Koo, 2000b).
Black and green tea polyphenols protect in vitro red
blood cells against oxidative stressors (Grinberg et al.,
1997).
Regular tea intake did not alter in vivo lipid peroxi-
dation in intervention studies. Urinary F2-isoprostanes
were measured following 7 days (1000 ml=day of each
black and green tea) and 4 weeks of black tea
(1250 ml=day). The studies were performed with hyper-
tensive and hypercholesterolemic subjects, respectively.
No differences were found in urinary F2-isoprostane con-
centrations between the control and tea treatments. In
another clinical trial, black tea and onions (a good source
26 M. Gross
of quercetin) intake did not alter indices of oxidative
damage (O’Reilly et al., 2001). Thirty-two subjects were
given onion cakes and black tea for two weeks. Com-
pliance was verified by the measurement of plasma
quercetin levels. Neither plasma F2-isoprostanes nor
malondialdehyde-LDL autoantibodies were altered by
the flavonoid-rich dietary treatments. A human feeding
study did not find alterations in indices of oxidative
damage with the consumption of a green tea extract.
The trial had a crossover design with 3-week treatment
periods and a completely controlled diet. Hemoglobin
protein oxidation and urinary 8-oxo-deoxyguanosine
excretions did not change with treatment. Only plasma
antioxidant capacity increased postprandially with the
green tea extract treatment (Young et al., 2002). These
findings may suggest that the metabolism of catechins
precludes an antioxidant effect. However, glucuronides
are major metabolites of tea catechins in humans. These
metabolic products appear to retain their antioxidant
activity (Lu et al., 2003). Another factor may be the
extent of absorption. Blood concentrations of catechins
generally are quite low and may be ineffective.
Single clinical trials have shown in vivo antioxidant
activities for glabridin and parsley (a major source of api-
genin). The major flavonoid in licorice, glabridin, has
antioxidant and anti-atherosclerotic effects in human
subjects. A clinical trial with licorice extract found an
increase in LDL and plasma resistance to oxidation,
reduced plasma lipids, and reduced aggregation of
LDL particles (Fuhrman et al., 2002). A randomized
crossover clinical trial found mixed effects of parsley
on antioxidant enzymes. Subjects received the parsley
treatment for 1 week, and it resulted in an increase of
erythrocyte glutathione reductase and superoxide dismu-
tase activity. On the other hand, erythrocyte catalase and
glutathione peroxidase activities were unchanged by the
intervention (Nielsen et al., 1999).
The results of human studies are mixed for the in vivo
antioxidant activity of flavonoids. The specific flavonoid,
its metabolism and source of oxidative stress may be fac-
tors in the efficacy of flavonoids as in vivo antioxidants.
Further trials are necessary for a thorough evaluation of
the in vivo antioxidant activity of flavonoids.
Platelet activity
Platelets have a central role in the pathogenesis of coron-
ary heart disease. Activation of these cellular components
releases a wide variety of proatherogenic factors and is a
central feature in the development of thrombosis during
acute coronary heart disease events. Platelet activity is
diminished by aspirin, which has been recommended as a
preventative agent in the general population for many
years. Flavonoid exposure also may diminish platelet
activity and reduce the risk of coronary heart disease.
The moderate consumption of red wine, a beverage
high in flavonoids, has been associated with a low risk
of cardiovascular disease. A portion of this beneficial
effect has been attributed to the alcohol in wine, which
may alter blood lipoprotein levels including an increase
in high-density lipoprotein (HDL) concentrations
(Vogel, 2002). However, the flavonoid content of red
wine also has been indicated as another major factor in
the prevention of cardiovascular disease. Dealcoholized
red wine inhibits the expression of epinephrine-induced
platelet antigens in vitro but did not affect the acti-
vation-dependent platelet antigen expression in either
unstimulated platelets or after ex vivo activation with epi-
nephrine (Rein et al., 2000). Many of the flavonoids in
wine also are contained in purple grape juice. Thus, inter-
est in the influence of purple grape juice on the risk of
cardiovascular disease has grown in recent years. Purple
grape juice and its flavonoids have antiplatelet and anti-
oxidant activities. Several studies have shown an inhi-
bition of platelet activity in the Folts dog model of
acute platelet thrombus formation by purple grape juice
and quercetin, a constituent of grape juice (Demrow
et al., 1995; Folts et al., 1982). Purple grape juice inhibits
platelet activity in dogs, monkeys, and humans (Folts,
2002). Further studies have identified the inhibition of
platelet aggregation as occurring through an enhance-
ment of platelet-derived nitric oxide release, a central
regulator of platelet activity, and a reduction in super-
oxide production in vitro (Freedman et al., 2001).
Consumption of purple grape juice (7 ml kg
1 day
1)
for 14 days resulted in the ex vivo reduction of platelet
aggregation, an increase in NO release, and a decrease
in superoxide formation (Freedman et al., 2001). A feed-
ing study investigated the effect of flavonoid-rich foods
on hemostasis. The study fed onions, a source of quer-
cetin, and parsley, a source of apigenin, for treatment
periods of 7 days. No effect was found on ex vivo platelet
aggregation, thromboxane B2, and factor VII (Janssen et
al., 1998). A flavonoid-rich beverage, tea, did not alter
platelet activity in cardiovascular disease patients (Duffy
et al., 2001b). Platelet activity was examined within 2 h
following the consumption of tea (450 ml) and after a
long-term exposure (900 ml=day for 4 weeks). A response
may have been mitigated as a result of aspirin use and
antiplatelet agent usage by many of the patients. Green
tea catechins may inhibit platelet aggregation by the inhi-
bition of an increase in cytoplasmic calcium (Kang et al.,
2001).
Thus, the results are mixed for a relationship between
flavonoid-rich food consumption and an inhibition of
platelet activity: however, the relationship may be com-
plex. A comparison of results of platelet studies with
foods and purified flavonoids suggests synergy between
flavonoids in the inhibition of platelet activity (Violi
et al., 2002). Metabolism of flavonoids also may
influence their antiplatelet activities, as some studies
 Flavonoids and cardiovascular disease
suggest that quercetin is not active in vivo. Further stu-
dies are necessary for an understanding of the antiplate-
let activities of flavonoid-rich foods. In particular,
identification of the agents in purple grape juice and a
better understanding of flavonoid metabolism are impor-
tant areas of investigation. Various in vitro studies have
shown antiplatelet activity for various purified flavo-
noids and have been described previously (Folts, 2002).
Vessel function
Blood vessel function has been characterized by flow-
mediated vasomotor responses and arterial stiffness.
These characteristics typically are measured with vascu-
lar ultrasonography and have been related to the risk
of cardiovascular disease. Vasomotor responses are
reduced and arterial stiffness increases when there is vas-
cular endothelial dysfunction as commonly occurs with
atherosclerosis and cardiovascular disease (Tiritilli,
1998). Several studies have shown that vasomotor
responses and arterial stiffness can be improved in coron-
ary artery disease patients with drug usage (statins) and
dietary manipulation, especially antioxidant intakes
(Keaney & Vita, 1995). One group of antioxidant intakes
that improves vessel function has been flavonoid-rich
foods. The flavonoid-rich beverage, tea, increases the
vasodilation response of cardiovascular disease patients
(Duffy et al., 2001a). The response is improved within
2 h following the consumption of tea (450 ml) and after
long-term exposure (900 ml=day for 4 weeks). Results
are similar when purple grape juice is given to coronary
artery disease patients. Consumption of 7.7 ml kg
1
day
1 of purple grape juice for 14 days increases flow-
mediated vasodilation from 2.2  2.9% to 6.4  4.7%
(Stein et al., 1999). In subjects without cardiovascular
disease, black tea intake (5 cups=day) improves brachial
artery reactivity in hypercholesterolemic and hypertrigly-
ceridemic subjects (Hodgson et al., 2002). Endothelial-
dependent dilation is increases by 2.3% following 4
weeks of treatment. However, this effect is primarily a
result of a large change in one individual, and the extent
of effect in healthy individuals is debatable. The isofla-
vones biochainin and fornonenetin (precursors of genis-
tein and daidzein, respectively) affected vessel function
in a human placebo-controlled clinical trial. The trial
included both men and postmenopausal women. Treat-
ment with formononetin reduces arterial stiffness with
a reduction in peripheral resistance (Teede et al., 2003).
Thus, several flavonoid-rich foods and flavonoids have
shown an effect on vessel function, which may reduce
the risk of coronary heart disease.
Moderate red wine consumption has been associated
with a decrease in the risk of coronary artery disease:
the French Paradox (Kannel & Ellison, 1996; Belleville,
2002). One mechanism for this association may be
an improvement in vessel function. Red wine and
27
dealcoholized red wine intakes have improved vessel
function. The flavonoid content varies significantly
between red wines and has been associated with their
effect on the vasodilation of rabbit aortic rings. Total
phenolic content is associated with vasodilation activity
and antioxidant activity, which may be the mechanism
for vasodilation. Typical phenolic compounds contained
in red wines include quercetin, kaempferol, isorhamne-
tin, (þ)-catechin, (
)-epicatechin, p-coumaric acid, caf-
feic acid, caftaric acid, trans-resveratrol, cis-resveratrol,
trans-resveratrol glucoside, and free and conjugated myr-
icetin. Gallic acid is also a phenolic-associated com-
pound found in red wines (Burns et al., 2000). Thus,
these flavonoids, separately or together, may be the
active agents in the improvement of vessel function.
Resveratrol enhances the expression of nitric oxide
synthase (NOS) in human endothelial cells (Leikert
et al., 2002; Wallerath et al., 2002). The induction of
NOS is the primary mechanism for vasodilation
(McHugh & Cheek, 1998). Flavonoids may maintain
stability of the NOS system, which improves NO pro-
duction and reduces superoxide production (Freedman
et al., 2001). This activity may occur through the antioxi-
dant activity of the flavonoids and regulation of signal
pathways. The mechanisms of myricetin involves an
induction of calcium influx, which subsequently induced
the activation of phospholipase A2 and the cyclooxygen-
ase pathway with the release of thromboxane A2 (Jimenez
et al., 1999). Another mechanism that may be active is
inhibition of the NFjB=inhibitor-jB (IjB) system, which
is a key regulator of numerous genes that respond to oxi-
dative stress. For instance, its activation is associated
with monocyte adhesion to vascular cells (Tsai et al.,
1999; Kim et al., 2003). This system is regulated by cyto-
kines, such as TNF-a and, importantly, redox status.
Thus, it can coordinate several proatherogenic events
including changes in vessel function. These regulatory
mechanisms may individually or together influence vessel
function.
Additional evidence for a flavonoid effect on vessel
function comes from several animal models. In rabbit
vessels, quercetin induced vasorelaxation of conductance
and resistance vessels, which were unaffected by a mod-
erate red wine exposure (Rendig et al., 2001). In reperfu-
sion injury experiments, quercetin decreased superoxide
anion exposures and increased nitric oxide, a cytoprotec-
tive agent. Each of these events is tracked in a rabbit hin-
dlimb ischemia model (Huk et al., 1998). Flavonols and
flavanols induced vasorelaxation in isolated rat thoracic
aorta (Chan et al., 2000). The treatment of rats with red
wine polyphenols lowered systolic blood pressure,
increased endothelium-dependent relaxation, and
increased inducible NO synthase and cyclooxygenase
(Diebolt et al., 2001).
The relaxation of vascular smooth muscle cells in rat
aorta ring preparations by quercetin and rutin prompted
28 M. Gross
the use of these agents in a clinical setting (Fusi et al.,
2003). Two studies indicate that venous insufficiency
may be improved through treatment with rutin and its
derivatives (Cataldi et al., 2001; Petruzzellis et al.,
2002). An extract of Ruscus aculeatus and hesperidin
methylchalcone inhibits the activation of endothelial cells
by hypoxia and may account for the efficacy of these
substances in the treatment of venous insufficiency
(Bouaziz et al., 1999).
The promotion of vessel function by flavonoids is sup-
ported by both animal model and human studies.
Mechanisms of action have been identified, and their
activity may have clinical relevance in the regulation of
vessel function, but these aspects of flavonoid activity
require further validation. Further studies are needed
for the identification of subjects whose vessel function
will benefit from an enhancement in flavonoid intake.
The amount, type, and form of flavonoid intake also
require further definition.
Epidemiology
Several epidemiologic studies have associated flavonoid
intake with a low risk of cardiovascular disease. One
such study found a relative risk of nonfatal myocardial
infarction of 0.77 among male smokers was high as com-
pared with a low intake of flavonols and flavones (Hirvo-
nen et al., 2001). The risk of aortic calcification is lower
among subjects with a high tea intake ( > 4 cups=day) as
compared to nondrinkers in the Rotterdam Study. The
odds ratio is 0.31 (CL ¼ 0.16 to 0.59) following adjust-
ment for age, sex, body mass index, smoking, education,
and the intakes of alcohol, coffee, vitamin antioxidants,
and several components of diet (Geleijnse et al., 1999).
The Physicians Health Study did not find an association
between flavonol and flavone intake and the risk of non-
fatal coronary heart disease. A nonsignificant association
was found between flavonol and flavone intake and cor-
onary mortality rates (Rimm et al., 1996) in a prospective
study with 4 years of follow-up. A prospective study of
postmenopausal women found an inverse relationship
between catechin intake and coronary heart disease
death. In 12 years of follow-up, 767 cases occurred
among 34,492 participants. Individuals with the highest
catechin intake have a risk ratio of 0.76 (Arts et al.,
2001). A study of Finnish men and women found a lower
risk of several chronic diseases among subjects with a
high versus low intake of flavonoids. Subjects with the
highest intakes of quercetin had a relative risk of 0.79
(CI ¼ 0.63 to 0.99) for mortality from ischemic heart dis-
ease (Knekt et al., 2002). A similar level of relative risk
for cerebrovascular disease was found for the highest
intakes of kaempferol, naringenin, and hesperitin
(Gebhardt, 2003). These results generally indicate an
association between flavonoid intake and a lower risk
of cardiovascular disease. However, several studies do
not show an association, and flavonoid intake may be
confounded by the intake of other dietary and other life-
style factors (Peters et al., 2001). In addition, the level of
intake varies significantly between countries and may be
the influencing factor in identification of associations.
The major food sources of flavonoids are tea, apples,
red wine, soy products, and onions. In a meta-analysis
of a more specific exposure, tea intake, high intakes
had a significant but relatively small protective effect
(RR ¼ 0.89) (Peters et al., 2001). Significant heterogen-
eity existed between studies, and some of these are not
considered in the analysis. Thus, overall the epidemiolo-
gic evidence suggests a slight reduction in risk of cardio-
vascular disease, but the issue remains debatable.
Blood cholesterol
Several studies have investigated the effect of flavonoids
on cholesterol synthesis and levels in cellular models,
experimental animals, and humans. The cellular models,
hepatocytes and HepG2 cells, have shown both stimu-
lation and inhibition of cholesterol synthesis by flavo-
noids, depending on the specific flavonoid and dosage
(Gebhardt, 2001). Quercetin, luteolin, and taxifolin
inhibit cholesterol synthesis, and kaempferol and myrice-
tin stimulate cholesterol synthesis. The effects may occur
through indirect mechanisms that modulate the complex
regulatory network of HMG-CoA reductase activity.
Luteolin may induce biliary secretion of cholesterol and
thereby reduce cholesterol levels. Dealcoholized red wine
extracts reduce the production of ApoB100 and increase
LDL receptor expression by HepG2 cells (Pal et al.,
2003). A hypocholesterolemic effect has been shown in
animal models for tea, naringenin, naringenin 7-O-cetyl
ether (Lee et al., 2003; Miura et al., 2001; Yang &
Koo, 2000a). Hesperidin supplementation lowered
plasma cholesterol levels in rats fed a high-cholesterol
diet (1%). It is accompanied by a reduction in HMG-
CoA reductase activity (Park et al., 2001). Hesperidin
is an inhibitor of lipases and may reduce plasma trigly-
cerides in rats. A reduction in plasma triglycerides is
found with a 10% dietary supplement (Kawaguchi
et al., 1997). Another study did not find an effect of
hesperidin on triglycerides (Park et al., 2001). In most
animal studies, flavonoids decreased total cholesterol
concentrations and increased the relative concentrations
of high-density lipoprotein concentrations and the
HDL:LDL ratio (Muramatsu et al., 1986; Matsumoto
et al., 1998; Vinson & Dabbagh, 1998). On the other
hand, the results of human observational studies have
been mixed. Black tea intake has been associated with
low cholesterol levels in six observational studies (Little
et al., 1966; Green & Jucha, 1986; Tuomilehto et al.,
1987; Prineas et al., 1980; Solvoll et al., 1989; Stensvold
 Flavonoids and cardiovascular disease
et al., 1992) and has not been associated with cholesterol
levels in many (10) other studies. Five of six clinical trials
did not show a change in cholesterol levels with treat-
ments of black tea (Bingham et al., 1997; Ishikawa
et al., 1997; van het Hof et al., 1997; McAnlis et al.,
1998; Princen et al., 1998; Davies et al., 2003). Similar
results are found with green tea, with mixed result for
observational studies (Kono et al., 1992, 1996; Imai &
Nakachi, 1995; Tsubono & Tsugane, 1997; Arai et al.,
2000; Tokunaga et al., 2002) and clinical trials (van het
Hof et al., 1997; Princen et al., 1998; Maron et al.,
2003). A theaflavin-enriched green tea extract decreased
cholesterol levels in a randomized controlled trial of Chi-
nese subjects consuming a low-saturated fat diet (Maron
et al., 2003). Both total cholesterol and LDL-cholesterol
are reduced by the treatment. These studies suggest that
certain flavonoids may have a hypocholesterolemic
effect, but the effect is dependent on dosage and the com-
plete diet. The higher dosages used in animal experiments
and extracts have hypocholesterolemic effects, whereas
typical human intakes generally did not have an effect.
Thus, typical dietary intakes appeared ineffective in
lowering cholesterol levels in human subjects.
Blood pressure
Several animal studies have shown a reduction in
blood pressure with flavonoid supplementation. The
long-term administration (15 weeks) of hesperidin and
glucosyl hesperidin lowered the blood pressure and
heart rate in spontaneously hypertensive rats (SHR)
but not in normotensive rats (WKY) (Ohtsuki et al.,
2002). N-nitro-L-arginine methyl ester (L-NAME)-
induced hypertension and its complications are reduced
in rats by quercetin supplementation. Quercetin supple-
mentation prevented increases in left ventricular and
kidney weight, proteinuria, renal lesions, and decreased
antioxidant status. Quercetin and its metabolites have
antihypertensive effects and provide end-organ protec-
tion (Duarte et al., 2002). These effects generally are
not found in human populations. Several studies eval-
uating blood pressure have not found an effect, and it
appears unlikely that typical flavonoid intakes signifi-
cantly reduce blood pressure in humans (Hodgson
et al., 1999; Washburn et al., 1999).
Conclusions
Recent advances in flavonoid research have included
substantial progress in the identification of the biological
activities of these compounds, especially in the area of
activities that may act in the prevention of cardiovascular
disease. Several areas of investigation appear promising
and may have substantial health effects. Flavonoids
29
may have several anti-atherosclerotic activities including
anti-inflammatory, antioxidant, antiproliferative, anti-
platelet, and provessel function activities. Cholesterol-
lowering and antihypertensive effects appear minimal
for the flavonoids. Many of these activities have been
demonstrated in cellular systems and experimental ani-
mals. Human studies have been performed in the evalu-
ation of a few of these activities. However, further
human studies are essential for the establishment of most
flavonoid effects and evaluation of their health impact.
In particular, studies are essential for the evaluation of
dosage effects, which generally are lacking in current stu-
dies. Design and analysis of such experiments should
consider the possible pleiotropic effects of flavonoids
and the possibility that their cumulative effect will affect
the risk of cardiovascular disease more than individual
effects, such as an improvement in vessel function.
Another important area that affects interpretation of
such studies is the need for a better understanding of fla-
vonoid absorption and metabolism. Although some pro-
gress has been made in this area, flavonoid metabolism
can be extensive, and the actual flavonoid or metabolite
with biological activity in vivo generally is not known.
Identification of the flavonoids occurring in vivo and
their biological activities is an important next step in
understanding the role of flavonoids in the prevention
of cardiovascular disease. Another limitation of many
current human studies is that generally flavonoid-rich
foods have been evaluated, and these often contain a var-
iety of flavonoids and phytochemicals. Thus, identifi-
cation of a specific flavonoid that precipitates the
effects has been difficult.
The identification of flavonoid-specific effects in
humans, the active compounds, and their affect on the
risk of cardiovascular disease requires further progress
in several areas. Following these developments, it should
be possible to design clinical trials that can identify the
human health effects of specific flavonoids.
References
Anthony MS, Clarkson TB, Williams JK (1998): Effects of
soy isoflavones on atherosclerosis: Potential mechan-
isms. Am J Clin Nutr 68: 1390S–1393S.
Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R,
Kinae N (2000): Dietary intakes of flavonols, flavones
and isoflavones by Japanese women and the inverse
correlation between quercetin intake and plasma LDL
cholesterol concentration. J Nutr 130: 2243.
Arima H, Ashida H, Danno G (2002): Rutin-enhanced anti-
bacterial activities of flavonoids against Bacillus cereus
and Salmonella enteritidis. Biosci Biotechnol Biochem
66: 1009.
Arts IC, Jacobs DR Jr, Harnack LJ, Gross M, Folsom AR
(2001): Dietary catechins in relation to coronary heart
30 M. Gross
disease death among postmenopausal women. Epidemio-
logy 12: 668.
Belleville J (2002): The French paradox: Possible involve-
ment of ethanol in the protective effect against cardio-
vascular diseases. Nutrition 18: 173.
Bingham SA, Vorster H, Jerling JC, Magee E, Mulligan A,
Runswick SA, Cummings JH (1997): Effect of black tea
drinking on blood lipids, blood pressure and aspects of
bowel habit. Br J Nutr 78: 41.
Binsack R, Boersma BJ, Patel RP, Kirk M, White CR,
Darley-Usmar V, Barnes S, Zhou F, Parks DA
(2001): Enhanced antioxidant activity after chlorination
of quercetin by hypochlorous acid. Alcohol Clin Exp
Res 25: 434.
Bouaziz N, Michiels C, Janssens D, Berna N, Eliaers F,
Panconi E, Remacle J (1999): Effect of Ruscus extract
and hesperidin methylchalcone on hypoxia-induced
activation of endothelial cells. Int Angiol 18: 306.
Boyle SP, Dobson VL, Duthie SJ, Hinselwood DC, Kyle
JA, Collins AR (2000): Bioavailability and efficiency
of rutin as an antioxidant: A human supplementation
study. Eur J Clin Nutr 54: 774.
Burns J, Gardner PT, O’Neil J, Crawford S, Morecroft I,
McPhail DB, Lister C, Matthews D, MacLean MR,
Lean ME, Duthie GG, Crozier A (2000): Relationship
among antioxidant activity, vasodilation capacity, and
phenolic content of red wines. J Agric Food Chem 48: 220.
Carluccio MA, Siculella L, Ancora MA, Massaro M, Sco-
ditti E, Storelli C, Visioli F, Distante A, De Caterina
R (2003): Olive oil and red wine antioxidant polyphe-
nols inhibit endothelial activation: Antiatherogenic
properties of Mediterranean diet phytochemicals.
Arterioscler Thromb Vasc Biol 23: 622.
Cataldi A, Gasbarro V, Viaggi R, Soverini R, Gresta E,
Mascoli F (2001): [Effectiveness of the combination
of alpha tocopherol, rutin, melilotus, and Centella
asiatica in the treatment of patients with chronic venous
insufficiency]. Minerva Cardioangiol 49: 159.
Chan EC, Pannangpetch P, Woodman OL (2000): Relax-
ation to flavones and flavonols in rat isolated thoracic
aorta: Mechanism of action and structure-activity rela-
tionships. J Cardiovasc Pharmacol 35: 326.
Chen YC, Shen SC, Lee WR, Hou WC, Yang LL, Lee TJ
(2001): Inhibition of nitric oxide synthase inhibitors
and lipopolysaccharide induced inducible NOS and
cyclooxygenase-2 gene expressions by rutin, quercetin,
and quercetin pentaacetate in RAW 264.7 macro-
phages. J Cell Biochem 82: 537.
Choi JH, Chang HW, Rhee SJ (2002): Effect of green
tea catechin on arachidonic acid cascade in chronic
cadmium-poisoned rats. Asia Pac J Clin Nutr 11: 292.
Davies MJ, Judd JT, Baer DJ, Clevidence BA, Paul DR,
Edwards AJ, Wiseman SA, Muesing RA, Chen SC
(2003): Black tea consumption reduces total and LDL
cholesterol in mildly hypercholesterolemic adults. J
Nutr 133: 3298S.
Demrow HS, Slane PR, Folts JD (1995): Administration
of wine and grape juice inhibits in vivo platelet activity
and thrombosis in stenosed canine coronary arteries.
Circulation 91: 1182.
Diebolt M, Bucher B, Andriantsitohaina R (2001): Wine
polyphenols decrease blood pressure, improve NO
vasodilatation, and induce gene expression. Hyperten-
sion 38: 159.
Duarte J, Jimenez R, O’Valle F, Galisteo M, Perez-Palencia
R, Vargas F, Perez-Vizcaino F, Zarzuelo A, Tamargo J
(2002): Protective effects of the flavonoid quercetin in
chronic nitric oxide deficient rats. J Hypertens 20: 1843.
Duffy SJ, Keaney JF Jr, Holbrook M, Gokce N, Swerdloff
PL, Frei B, Vita JA (2001a): Short- and long-term black
tea consumption reverses endothelial dysfunction in
patients with coronary artery disease. Circulation 104:
151.
Duffy SJ, Vita JA, Holbrook M, Swerdloff PL, Keaney JF
Jr (2001b): Effect of acute and chronic tea consumption
on platelet aggregation in patients with coronary artery
disease. Arterioscler Thromb Vasc Biol 21: 1084.
Filipe P, Morliere P, Patterson LK, Hug GL, Maziere JC,
Maziere C, Freitas JP, Fernandes A, Santus R
(2002a): Mechanisms of flavonoid repair reactions with
amino acid radicals in models of biological systems: A
pulse radiolysis study in micelles and human serum
albumin. Biochim Biophys Acta 1572: 150.
Filipe P, Morliere P, Patterson LK, Hug GL, Maziere JC,
Maziere C, Freitas JP, Fernandes A, Santus R
(2002b): Repair of amino acid radicals of apolipopro-
tein B100 of low-density lipoproteins by flavonoids. A
pulse radiolysis study with quercetin and rutin. Bio-
chemistry 41: 11057.
Folts JD (2002): Potential health benefits from the flavo-
noids in grape products on vascular disease. Adv Exp
Med Biol 505: 95.
Folts JD, Gallagher K, Rowe GG (1982): Blood flow reduc-
tions in stenosed canine coronary arteries: Vasospasm
or platelet aggregation? Circulation 65: 248.
Frank J, Kamal-Eldin A, Lundh T, Maatta K, Torronen R,
Vessby B (2002): Effects of dietary anthocyanins on
tocopherols and lipids in rats. J Agric Food Chem 50:
7226.
Freedman JE, Parker C 3rd, Li L, Perlman JA, Frei B, Iva-
nov V, Deak LR, Iafrati MD, Folts JD (2001): Select
flavonoids and whole juice from purple grapes inhibit
platelet function and enhance nitric oxide release. Cir-
culation 103: 2792.
Fuhrman B, Aviram M (2001): Flavonoids protect LDL
from oxidation and attenuate atherosclerosis. Curr
Opin Lipidol 12: 41.
Fuhrman B, Volkova N, Kaplan M, Presser D, Attias J,
Hayek T, Aviram M (2002): Antiatherosclerotic
effects of licorice extract supplementation on hyper-
cholesterolemic patients: Increased resistance of LDL
to atherogenic modifications, reduced plasma lipid
 Flavonoids and cardiovascular disease
levels, and decreased systolic blood pressure. Nutrition
18: 268.
Fusi F, Saponara S, Pessina F, Gorelli B, Sgaragli G (2003):
Effects of quercetin and rutin on vascular preparations:
A comparison between mechanical and electrophysiolo-
gical phenomena. Eur J Nutr 42: 10.
Gao Z, Xu H, Huang K (2002): Effects of rutin supplemen-
tation on antioxidant status and iron, copper, and zinc
contents in mouse liver and brain. Biol Trace Elem Res
88: 271.
Gebhardt R (2001): Anticholestatic activity of flavonoids
from artichoke (Cynara scolymus L.) and of their meta-
bolites. Med Sci Monit 7 (Suppl 1): 316.
Gebhardt R (2003): Variable influence of kaempferol and
myricetin on in vitro hepatocellular cholesterol bio-
synthesis. Planta Med 69: 1071.
Geleijnse JM, Launer LJ, Hofman A, Pols HA, Witteman
JC (1999): Tea flavonoids may protect against athero-
sclerosis: The Rotterdam Study. Arch Intern Med 159:
2170.
Gordon MH, Roedig-Penman A (1998): Antioxidant
activity of quercetin and myricetin in liposomes. Chem
Phys Lipids 97: 79.
Green MS, Jucha E (1986): Association of serum lipids with
coffee, tea, and egg consumption in free-living subjects.
J Epidemiol Community Health 40: 324.
Grinberg LN, Newmark H, Kitrossky N, Rahamim E, Che-
vion M, Rachmilewitz EA (1997): Protective effects of
tea polyphenols against oxidative damage to red blood
cells. Biochem Pharmacol 54: 973.
Guardia T, Rotelli AE, Juarez AO, Pelzer LE (2001): Anti-
inflammatory properties of plant flavonoids. Effects of
rutin, quercetin and hesperidin on adjuvant arthritis in
rat. Farmaco 56: 683.
Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P,
Coleman R, Elis A, Aviram M (1997): Reduced pro-
gression of atherosclerosis in apolipoprotein E-deficient
mice following consumption of red wine, or its polyphe-
nols quercetin or catechin, is associated with reduced
susceptibility of LDL to oxidation and aggregation.
Arterioscler Thromb Vasc Biol 17: 2744.
Hiermann A, Schramm HW, Laufer S (1998): Anti-inflam-
matory activity of myricetin-3-O-beta-D-glucuronide
and related compounds. Inflamm Res 47: 421.
Hirvonen T, Pietinen P, Virtanen M, Ovaskainen ML, Hak-
kinen S, Albanes D, Virtamo J (2001): Intake of flavo-
nols and flavones and risk of coronary heart disease in
male smokers. Epidemiology 12: 62.
Hodgson JM, Puddey IB, Beilin LJ, Mori TA, Burke V,
Croft KD, Rogers PB (1999): Effects of isoflavonoids
on blood pressure in subjects with high-normal ambu-
latory blood pressure levels: A randomized controlled
trial. Am J Hypertens 12: 47.
Hodgson JM, Puddey IB, Burke V, Watts GF, Beilin LJ
(2002): Regular ingestion of black tea improves brachial
artery vasodilator function. Clin Sci (London) 102: 195.
31
Huk I, Brovkovych V, Nanobash Vili J, Weigel G, Neu-
mayer C, Partyka L, Patton S, Malinski T (1998): Bio-
flavonoid quercetin scavenges superoxide and increases
nitric oxide concentration in ischaemia-reperfusion
injury: An experimental study. Br J Surg 85: 1080.
Hwang KC, Lee KH, Jang Y, Yun YP, Chung KH (2002):
Epigallocatechin-3-gallate inhibits basic fibroblast
growth factor-induced intracellular signaling transduc-
tion pathway in rat aortic smooth muscle cells. J Cardio-
vasc Pharmacol 39: 271.
Igarashi K, Kimura Y, Takenaka A (2000): Preventive
effects of dietary cabbage acylated anthocyanins on
paraquat-induced oxidative stress in rats. Biosci Bio-
technol Biochem 64: 1600.
Iijima K, Yoshizumi M, Hashimoto M, Akishita M, Kozaki
K, Ako J, Watanabe T, Ohike Y, Son B, Yu J, Naka-
hara K, Ouchi Y (2002): Red wine polyphenols inhibit
vascular smooth muscle cell migration through two
distinct signaling pathways. Circulation 105: 2404.
Imai K, Nakachi K (1995): Cross sectional study of effects
of drinking green tea on cardiovascular and liver
diseases. Br Med J 310: 693.
Ishikawa T, Suzukawa M, Ito T, Yoshida H, Ayaori M,
Nishiwaki M, Yonemura A, Hara Y, Nakamura H
(1997): Effect of tea flavonoid supplementation on the
susceptibility of low-density lipoprotein to oxidative
modification. Am J Clin Nutr 66: 261.
Ishiwa J, Sato T, Mimaki Y, Sashida Y, Yano M, Ito A
(2000): A citrus flavonoid, nobiletin, suppresses pro-
duction and gene expression of matrix metalloprotei-
nase 9=gelatinase B in rabbit synovial fibroblasts. J
Rheumatol 27: 20.
Janssen K, Mensink RP, Cox FJ, Harryvan JL, Hovenier R,
Hollman PC, Katan MB (1998): Effects of the flavo-
noids quercetin and apigenin on hemostasis in healthy
volunteers: Results from an in vitro and a dietary sup-
plement study. Am J Clin Nutr 67: 255.
Jimenez R, Andriambeloson E, Duarte J, Andriantsitohaina
R, Jimenez J, Perez-Vizcaino F, Zarzuelo A, Tamargo J
(1999): Involvement of thromboxane A2 in the endo-
thelium-dependent contractions induced by myricetin
in rat isolated aorta. Br J Pharmacol 127: 1539.
Kahkonen MP, Heinonen M (2003): Antioxidant activity of
anthocyanins and their aglycons. J Agric Food Chem
51: 628.
Kang WS, Chung KH, Chung JH, Lee JY, Park JB, Zhang
YH, Yoo HS, Yun YP (2001): Antiplatelet activity of
green tea catechins is mediated by inhibition of cyto-
plasmic calcium increase. J Cardiovasc Pharmacol 38:
875.
Kannel WB, Ellison RC (1996): Alcohol and coronary heart
disease: The evidence for a protective effect. Clin Chim
Acta 246: 59.
Kapiotis S, Hermann M, Held I, Seelos C, Ehringer H,
Gmeiner BM (1997): Genistein, the dietary-derived
angiogenesis inhibitor, prevents LDL oxidation and
32 M. Gross
protects endothelial cells from damage by atherogenic
LDL. Arterioscler Thromb Vasc Biol 17: 2868.
Kawaguchi K, Mizuno T, Aida K, Uchino K (1997):
Hesperidin as an inhibitor of lipases from porcine
pancreas and Pseudomonas. Biosci Biotechnol Biochem
61: 102.
Keaney JF Jr, Vita JA (1995): Atherosclerosis, oxidative
stress, and antioxidant protection in endothelium-
derived relaxing factor action. Prog Cardiovasc Dis
38: 129.
Kessler M, Ubeaud G, Jung L (2003): Anti- and pro-oxidant
activity of rutin and quercetin derivatives. J Pharm
Pharmacol 55: 131.
Kim TJ, Zhang YH, Kim Y, Lee CK, Lee MK, Hong JT,
Yun YP (2002): Effects of apigenin on the serum- and
platelet derived growth factor-BB-induced proliferation
of rat aortic vascular smooth muscle cells. Planta Med
68: 605.
Kim SH, Shin KJ, Kim D, Kim YH, Han MS, Lee TG, Kim
E, Ryu SH, Suh PG (2003): Luteolin inhibits the
nuclear factor-kappa B transcriptional activity in Rat-
1 fibroblasts. Biochem Pharmacol 66: 955.
Kimata M, Inagaki N, Nagai H (2000a): Effects of luteolin
and other flavonoids on IgE-mediated allergic reac-
tions. Planta Med 66: 25.
Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N,
Nagai H (2000b): Effects of luteolin, quercetin and bai-
calein on immunoglobulin E-mediated mediator release
from human cultured mast cells. Clin Exp Allergy 30:
501.
Knekt P, Kumpulainen J, Jarvinen R, Rissanen H, Helio-
vaara M, Reunanen A, Hakulinen T, Aromaa A
(2002): Flavonoid intake and risk of chronic diseases.
Am J Clin Nutr 76: 560.
Knight DC, Eden JA (1996): A review of the clinical effects
of phytoestrogens. Obstet Gynecol 87: 897.
Kono S, Shinchi K, Ikeda N, Yanai F, Imanishi K (1992):
Green tea consumption and serum lipid profiles: A
cross-sectional study in northern Kyushu, Japan. Prev
Med 21: 526.
Kono S, Shinchi K, Wakabayashi K, Honjo S, Todoroki I,
Sakurai Y, Imanishi K, Nishikawa H, Ogawa S, Kat-
surada M (1996): Relation of green tea consumption
to serum lipids and lipoproteins in Japanese men. J Epi-
demiol 6: 128.
Kotanidou A, Xagorari A, Bagli E, Kitsanta P, Fotsis T,
Papapetropoulos A, Roussos C (2002): Luteolin
reduces lipopolysaccharide-induced lethal toxicity and
expression of proinflammatory molecules in mice. Am
J Respir Crit Care Med 165: 818.
Lee MK, Moon SS, Lee SE, Bok SH, Jeong TS, Park YB,
Choi MS (2003): Naringenin 7-O-cetyl ether as inhibi-
tor of HMG-CoA reductase and modulator of plasma
and hepatic lipids in high cholesterol-fed rats. Bioorg
Med Chem 11: 393.
Leikert JF, Rathel TR, Wohlfart P, Cheynier V, Vollmar
AM, Dirsch VM (2002): Red wine polyphenols enhance
endothelial nitric oxide synthase expression and sub-
sequent nitric oxide release from endothelial cells.
Circulation 106, 1614.
Libby P, Ridker PM (2004): Inflammation and atheroscler-
osis: role of C-reactive protein in risk assessment. Am J
Med 116 (Suppl 6 A): 9S.
Lin N, Sato T, Takayama Y, Mimaki Y, Sashida Y, Yano
M, Ito A (2003): Novel anti-inflammatory actions of
nobiletin, a citrus polymethoxy flavonoid, on human
synovial fibroblasts and mouse macrophages. Biochem
Pharmacol 65: 2065.
Lissin LW, Cooke JP (2000): Phytoestrogens and cardio-
vascular health. J Am Coll Cardiol 35: 1403.
Little JA, Shanoff HM, Csima A, Toronto MA, Yano R
(1966): Coffee and serum-lipids in coronary heart-
disease. Lancet 1: 732.
Lu H, Meng X, Li C, Sang S, Patten C, Sheng S, Hong J,
Bai N, Winnik B, Ho CT, Yang CS (2003):
Glucuronides of tea catechins: Enzymology of bio-
synthesis and biological activities. Drug Metab Dispos
31: 452.
Maron DJ, Lu GP, Cai NS, Wu ZG, Li YH, Chen H, Zhu
JQ, Jin XJ, Wouters BC, Zhao J (2003): Cholesterol-
lowering effect of a theaflavin-enriched green tea
extract: A randomized controlled trial. Arch Intern
Med 163: 1448.
Matsumoto N, Okushio K, Hara Y (1998): Effect of black
tea polyphenols on plasma lipids in cholesterol-fed rats.
J Nutr Sci Vitaminol (Tokyo) 44: 337.
Mazza G, Kay CD, Cottrell T, Holub BJ (2002): Absorp-
tion of anthocyanins from blueberries and serum anti-
oxidant status in human subjects. J Agric Food Chem
50: 7731.
McAnlis GT, McEneny J, Pearce J, Young IS (1998): Black tea
consumption does not protect low density lipoprotein
from oxidative modification. Eur J Clin Nutr 52: 202.
McHugh J, Cheek DJ (1998): Nitric oxide and regulation of
vascular tone: Pharmacological and physiological con-
siderations. Am J Crit Care 7: 131.
Milde J, Elstner EF, Grassmann J (2004): Synergistic inhi-
bition of low-density lipoprotein oxidation by rutin,
gamma-terpinene, and ascorbic acid. Phytomedicine
11: 105.
Mira L, Fernandez MT, Santos M, Rocha R, Florencio
MH, Jennings KR (2002): Interactions of flavonoids
with iron and copper ions: A mechanism for their anti-
oxidant activity. Free Radic Res 36: 1199.
Miura Y, Chiba T, Tomita I, Koizumi H, Miura S,
Umegaki K, Hara Y, Ikeda M, Tomita T (2001): Tea
catechins prevent the development of atherosclerosis
in apoprotein E-deficient mice. J Nutr 131: 27.
Morel I, Abalea V, Sergent O, Cillard P, Cillard J (1998):
Involvement of phenoxyl radical intermediates in lipid
 Flavonoids and cardiovascular disease
antioxidant action of myricetin in iron-treated rat hepa-
tocyte culture. Biochem Pharmacol 55: 1399.
Murakami A, Nakamura Y, Ohto Y, Yano M, Koshiba T,
Koshimizu K, Tokuda H, Nishino H, Ohigashi H
(2000a): Suppressive effects of citrus fruits on free rad-
ical generation and nobiletin, an anti-inflammatory
polymethoxyflavonoid. Biofactors 12: 187.
Murakami A, Nakamura Y, Torikai K, Tanaka T, Koshiba
T, Koshimizu K, Kuwahara S, Takahashi Y, Ogawa K,
Yano M, Tokuda H, Nishino H, Mimaki Y, Sashida Y,
Kitanaka S, Ohigashi H (2000b): Inhibitory effect of
citrus nobiletin on phorbol ester-induced skin inflam-
mation, oxidative stress, and tumor promotion in mice.
Cancer Res 60: 5059.
Muramatsu K, Fukuyo M, Hara Y (1986): Effect of green
tea catechins on plasma cholesterol level in choles-
terol-fed rats. J Nutr Sci Vitaminol (Tokyo) 32: 613.
Natella F, Belelli F, Gentili V, Ursini F, Scaccini C (2002):
Grape seed proanthocyanidins prevent plasma post-
prandial oxidative stress in humans. J Agric Food Chem
50: 7720.
Nielsen SE, Young JF, Daneshvar B, Lauridsen ST, Knuth-
sen P, Sandstrom B, Dragsted LO (1999): Effect of
parsley (Petroselinum crispum) intake on urinary api-
genin excretion, blood antioxidant enzymes and bio-
markers for oxidative stress in human subjects. Br J
Nutr 81: 447.
Ohtsuki K, Abe A, Mitsuzuwi H, Kondo M, Uemura K,
Iwasaki Y, Kondo Y (2002): Effects of long-term
administration of hesperidin and glucosyl hesperidin
to spontaneously hypertensive rats. J Nutr Sci Vitami-
nol (Tokyo) 48: 420.
O’Reilly JD, Mallet AI, McAnlis GT, Young IS, Halliwell
B, Sanders TA, Wiseman H (2001): Consumption of
flavonoids in onions and black tea: Lack of effect on
F2-isoprostanes and autoantibodies to oxidized LDL
in healthy humans. Am J Clin Nutr 73: 1040.
Ostrakhovitch EA, Afanas’ev IB (2001): Oxidative stress in
rheumatoid arthritis leukocytes: Suppression by rutin
and other antioxidants and chelators. Biochem Pharma-
col 62: 743.
Pal S, Ho N, Santos C, Dubois P, Mamo J, Croft K, Allister
E (2003): Red wine polyphenolics increase LDL recep-
tor expression and activity and suppress the secretion of
ApoB100 from human HepG2 cells. J Nutr 133: 700.
Palmer H, Ohta M, Watanabe M, Suzuki T (2002): Oxidat-
ive stress-induced cellular damage caused by UV and
methyl viologen in Euglena gracilis and its suppression
with rutin. J Photochem Photobiol B 67: 116.
Park KY, Lee SH, Min BK, Lee KS, Choi JS, Chung SR,
Min KR, Kim Y (1999): Inhibitory effect of luteolin
40 -O-glucoside from Kummerowia striata and other fla-
vonoids on interleukin-5 bioactivity. Planta Med 65:
457.
Park YB, Do KM, Bok SH, Lee MK, Jeong TS, Choi MS
(2001): Interactive effect of hesperidin and vitamin E
33
supplements on cholesterol metabolism in high choles-
terol-fed rats. Int J Vitam Nutr Res 71: 36.
Peters U, Poole C, Arab L (2001): Does tea affect cardio-
vascular disease? A meta-analysis. Am J Epidemiol
154: 495.
Petruzzellis V, Troccoli T, Candiani C, Guarisco R, Lospal-
luti M, Belcaro G, Dugall M (2002): Oxerutins (Venor-
uton): Efficacy in chronic venous insufficiency—A
double-blind, randomized, controlled study. Angiology
53: 257.
Plumb GW, De Pascual-Teresa S, Santos-Buelga C, Chey-
nier V, Williamson G (1998): Antioxidant properties
of catechins and proanthocyanidins: Effect of polym-
erisation, galloylation and glycosylation. Free Radic
Res 29: 351.
Princen HM, van Duyvenvoorde W, Buytenhek R, Blonk C,
Tijburg LB, Langius JA, Meinders AE, Pijl H (1998):
No effect of consumption of green and black tea on
plasma lipid and antioxidant levels and on LDL oxi-
dation in smokers. Arterioscler Thromb Vasc Biol 18:
833.
Prineas RJ, Jacobs DR Jr, Crow RS, Blackburn H (1980):
Coffee, tea and VPB. J Chronic Dis 33: 67.
Qiusheng Z, Xiling S, Xubo, Meng S, Changhai W (2004):
Protective effects of luteolin-7-glucoside against liver
injury caused by carbon tetrachloride in rats. Pharmazie
59: 286.
Rein D, Paglieroni TG, Pearson DA, Wun T, Schmitz HH,
Gosselin R, Keen CL (2000): Cocoa and wine polyphe-
nols modulate platelet activation and function. J Nutr
130: 2120S.
Rendig SV, Symons JD, Longhurst JC, Amsterdam EA
(2001): Effects of red wine, alcohol, and quercetin on
coronary resistance and conductance arteries. J Cardio-
vasc Pharmacol 38: 219.
Ridker PM, Koenig W, Fuster V (2004): C-Reactive protein
and coronary heart disease. N Engl J Med 351: 295.
Rimm EB, Katan MB, Ascherio A, Stampfer MJ, Willett
WC (1996): Relation between intake of flavonoids
and risk for coronary heart disease in male health pro-
fessionals. Ann Intern Med 125: 384.
Rossi A, Serraino I, Dugo P, Di Paola R, Mondello L,
Genovese T, Morabito D, Dugo G, Sautebin L, Caputi
AP, Cuzzocrea S (2003): Protective effects of antho-
cyanins from blackberry in a rat model of acute lung
inflammation. Free Radic Res 37: 891.
Sato T, Koike L, Miyata Y, Hirata M, Mimaki Y, Sashida Y,
Yano M, Ito A (2002): Inhibition of activator protein-1
binding activity and phosphatidylinositol 3-kinase path-
way by nobiletin, a polymethoxy flavonoid, results in
augmentation of tissue inhibitor of metalloproteinases-
1 production and suppression of production of matrix
metalloproteinases-1 and -9 in human fibrosarcoma
HT-1080 cells. Cancer Res 62: 1025.
Scuro LS, Simioni PU, Grabriel DL, Saviani EE, Modolo
LV, Tamashiro WM, Salgado I (2004): Suppression of
34
nitric oxide production in mouse macrophages by soy-
bean flavonoids accumulated in response to nitroprus-
side and fungal elicitation. BMC Biochem 5: 5.
Seeram NP, Nair MG (2002): Inhibition of lipid peroxi-
dation and structure-activity-related studies of the diet-
ary constituents anthocyanins, anthocyanidins, and
catechins. J Agric Food Chem 50: 5308.
Seeram NP, Zhang Y, Nair MG (2003): Inhibition of pro-
liferation of human cancer cells and cyclooxygenase
enzymes by anthocyanidins and catechins. Nutr Cancer
46: 101.
Selloum L, Bouriche H, Tigrine C, Boudoukha C (2003):
Anti-inflammatory effect of rutin on rat paw oedema,
and on neutrophils chemotaxis and degranulation.
Exp Toxicol Pathol 54: 313.
Setchell KD, Cassidy A (1999): Dietary isoflavones: Biologi-
cal effects and relevance to human health. J Nutr 129:
758S.
Shen SC, Lee WR, Lin HY, Huang HC, Ko CH, Yang LL,
Chen YC (2002): In vitro and in vivo inhibitory activities
of rutin, wogonin, and quercetin on lipopolysaccharide-
induced nitric oxide and prostaglandin E(2) production.
Eur J Pharmacol 446: 187.
Solvoll K, Selmer R, Loken EB, Foss OP, Trygg K (1989):
Coffee, dietary habits, and serum cholesterol among
men and women 35–49 years of age. Am J Epidemiol
129: 1277.
St Clair R (1998): Cardiovascular effects of soybean phy-
toestrogens. Am J Cardiol 82: 40 S.
Stein JH, Keevil JG, Wiebe DA, Aeschlimann S, Folts JD
(1999): Purple grape juice improves endothelial func-
tion and reduces the susceptibility of LDL cholesterol
to oxidation in patients with coronary artery disease.
Circulation 100: 1050.
Stensvold I, Tverdal A, Solvoll K, Foss OP (1992): Tea con-
sumption. relationship to cholesterol, blood pressure,
and coronary and total mortality. Prev Med 21: 546.
Teede HJ, McGrath BP, DeSilva L, Cehun M, Fassoulakis
A, Nestel PJ (2003): Isoflavones reduce arterial
stiffness: A placebo-controlled study in men and post-
menopausal women. Arterioscler Thromb Vasc Biol
23: 1066.
Tham DM, Gardner CD, Haskell WL (1998): Clinical review
97: Potential health benefits of dietary phytoestrogens: A
review of the clinical, epidemiological, and mechanistic
evidence. J Clin Endocrinol Metab 83: 2223.
Thiagarajan G, Chandani S, Sundari CS, Rao SH, Kulkarni
AV, Balasubramanian D (2001): Antioxidant properties
of green and black tea, and their potential ability to retard
the progression of eye lens cataract. Exp Eye Res 73: 393.
Tiritilli A (1998): [Nitric oxide (NO), vascular protection
factor. Biology, physiological role and biochemistry of
NO]. Presse Med 27: 1061.
Tokunaga S, White IR, Frost C, Tanaka K, Kono S,
Tokudome S, Akamatsu T, Moriyama T, Zakouji H
(2002): Green tea consumption and serum lipids and
M. Gross
lipoproteins in a population of healthy workers in
Japan. Ann Epidemiol 12: 157.
Tsai SH, Liang YC, Lin-Shiau SY, Lin JK (1999): Sup-
pression of TNFalpha-mediated NFkappaB activity
by myricetin and other flavonoids through downregu-
lating the activity of IKK in ECV304 cells. J Cell Bio-
chem 74: 606.
Tsubono Y, Tsugane S (1997): Green tea intake in relation
to serum lipid levels in middle-aged Japanese men and
women. Ann Epidemiol 7: 280.
Tsuda T, Horio F, Osawa T (2000a): The role of anthocya-
nins as an antioxidant under oxidative stress in rats.
Biofactors 13: 133.
Tsuda T, Kato Y, Osawa T (2000b): Mechanism for the per-
oxynitrite scavenging activity by anthocyanins. FEBS
Lett 484: 207.
Tuomilehto J, Tanskanen A, Pietinen P, Aro A, Salonen JT,
Happonen P, Nissinen A, Puska P (1987): Coffee
consumption is correlated with serum cholesterol in
middle-aged Finnish men and women. J Epidemiol
Community Health 41: 237.
Ueda H, Yamazaki C, Yamazaki M (2002): Luteolin as an
anti-inflammatory and anti-allergic constituent of Peri-
lla frutescens. Biol Pharm Bull 25: 1197.
van het Hof KH, de Boer HS, Wiseman SA, Lien N, Westrate
JA, Tijburg LB (1997): Consumption of green or black
tea does not increase resistance of low-density lipopro-
tein to oxidation in humans. Am J Clin Nutr 66: 1125.
Vinson JA, Dabbagh YA (1998): Effect of green and black
tea supplementation on lipids, lipid oxidation and
fibrinogen in the hamster: Mechanisms for the epide-
miological benefits of tea drinking. FEBS Lett 433: 44.
Violi F, Pignatelli P, Pulcinelli FM (2002): Synergism
among flavonoids in inhibiting platelet aggregation
and H2O2 production. Circulation 105: e53.
Vogel RA (2002): Alcohol, heart disease, and mortality: A
review. Rev Cardiovasc Med 3: 7.
Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte
K, Forstermann U (2002): Resveratrol, a polyphenolic
phytoalexin present in red wine, enhances expression
and activity of endothelial nitric oxide synthase. Circu-
lation 106: 1652.
Wang J, Mazza G (2002): Inhibitory effects of anthocyanins
and other phenolic compounds on nitric oxide pro-
duction in LPS=IFN-gamma-activated RAW 264.7
macrophages. J Agric Food Chem 50: 850.
Washburn S, Burke GL, Morgan T, Anthony M (1999):
Effect of soy protein supplementation on serum lipo-
proteins, blood pressure, and menopausal symptoms
in perimenopausal women. Menopause 6: 7.
Wenisch C, Biffignandi PM (2001): Effect of bioflavonoids (tri-
hydroxyethylrutin and disodium flavodate) in vitro on neu-
trophil reactive oxygen production and phagocytic ability
assessed by flow cytometry. Curr Med Res Opin 17: 123.
Willerson JT, Ridker PM (2004): Inflammation as a cardio-
vascular risk factor. Circulation 109: II2.
 Flavonoids and cardiovascular disease
Xagorari A, Papapetropoulos A, Mauromatis A, Econo-
mou M, Fotsis T, Roussos C (2001): Luteolin inhibits
an endotoxin-stimulated phosphorylation cascade and
proinflammatory cytokine production in macrophages.
J Pharmacol Exp Ther 296: 181.
Xagorari A, Roussos C, Papapetropoulos A (2002): Inhi-
bition of LPS-stimulated pathways in macrophages by
the flavonoid luteolin. Br J Pharmacol 136: 1058.
Xu HX, Lee SF (2001): Activity of plant flavonoids against
antibiotic-resistant bacteria. Phytother Res 15: 39.
Yang TT, Koo MW (2000a): Chinese green tea lowers chol-
esterol level through an increase in fecal lipid excretion.
Life Sci 66: 411.
Yang TT, Koo MW (2000b): Inhibitory effect of Chinese
green tea on endothelial cell-induced LDL oxidation.
Atherosclerosis 148: 67.
35
Yoshida H, Ishikawa T, Hosoai H, Suzukawa M, Ayaori M,
Hisada T, Sawada S, Yonemura A, Higashi K, Ito T,
Nakajima K, Yamashita T, Tomiyasu K, Nishiwaki M,
Ohsuzu F, Nakamura H (1999): Inhibitory effect of tea
flavonoids on the ability of cells to oxidize low density
lipoprotein. Biochem Pharmacol 58: 1695.
Youdim KA, Martin A, Joseph JA (2000): Incorporation of
the elderberry anthocyanins by endothelial cells
increases protection against oxidative stress. Free Radic
Biol Med 29: 51.
Young JF, Dragstedt LO, Haraldsdottir J, Daneshvar B,
Kal MA, Loft S, Nilsson L, Nielsen SE, Mayer B,
Skibsted LH, Huynh-Ba T, Hermetter A, Sandstrom
B (2002): Green tea extract only affects markers of oxi-
dative status postprandially: Lasting antioxidant effect
of flavonoid-free diet. Br J Nutr 87: 343.