Cardiovascular Effects of Flavonoids

Abstract

Cardiovascular Disease (CVD) is the major cause of death worldwide, especially in Western society. Flavonoids are a large group of polyphenolic compounds widely distributed in plants, present in a considerable amount in fruit and vegetable. Several epidemiological studies found an inverse association between flavonoids intake and mortality by CVD. The antioxidant effect of flavonoids was considered the main mechanism of action of flavonoids and other polyphenols. In recent years, the role of modulation of signaling pathways by direct interaction of flavonoids with multiple protein targets, namely kinases, has been increasingly recognized and involved in their cardiovascular protective effect. There are strong evidence, in in vitro and animal experimental models, that some flavonoids induce vasodilator effects, improve endothelial dysfunction and insulin resistance, exert platelet antiaggregant and atheroprotective effects, and reduce blood pressure. Despite interacting with multiple targets, flavonoids are surprisingly safe. This article reviews the recent evidence about cardiovascular effects that support a beneficial role of flavonoids on CVD and the potential molecular targets involved.

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Cardiovascular effects of flavonoids
M. Sáncheza, M. Romeroa , M. Gómez-Guzmána, J. Tamargob,c, F. Pérez-Vizcainob,d and J. Duarte*,a,c
aDepartment of Pharmacology, School of Pharmacy, University of Granada, and Instituto de Investigación
Biosanitaria de Granada (ibs.GRANADA), Granada, Spain; b Department of Pharmacology, School of Medicine,
Complutense University of Madrid and Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid,
Spain; cCIBER-Enfermedades Cardiovasculares (CiberCV), Madrid, Spain; dCIBER Enfermedades Respiratorias
(Ciberes), Madrid, Spain.
Abstract: Cardiovascular disease (CVD) is the major cause of death worldwide, especially in Western
society. Flavonoids are a large group of polyphenolic compounds widely distributed in plants, present in
considerable amount in fruit and vegetable. Several epidemiological studies found an inverse association
between flavonoids intake and mortality by CVD. The antioxidant effect of flavonoids was considered the
main mechanism of action of flavonoids and other polyphenols. In recent years, the role of modulation of
signaling pathways by direct interaction of flavonoids with multiple protein targets, namely kinases, has
been increasingly recognized and involved in their cardiovascular protective effect. There are strong
evidences, in in vitro and animal experimental models, that some flavonoids induce vasodilator effects,
improve endothelial dysfunction and insulin resistance, exert platelet antiaggregant and atheroprotective
effects, and reduce blood pressure. Despite interacting with multiple targets, flavonoids are surprisingly
safe. This article reviews the recent evidences about cardiovascular effects that support a beneficial role
of flavonoids on CVD and the potential molecular targets involved.
Keywords: Flavonoids, endothelial function, hypertension, platelet aggregation, atherosclerosis, insulin resistance,
myocardial ischemia, stroke
INTRODUCTION
Flavonoids comprise a large group of
polyphenolic compounds chemically characterized,
sensu stricto, by the presence of a skeleton of 2-
phenyl-4H-1-benzopyrane, also kwown as 2-phenyl-
4H-chromene [1] (Fig. 1). They differ from
isoflavonoids and neoflavonoids, which derive from
3-phenylchromen-4-one and 4-phenylcoumarin,
respectively, and from chalcones and aurones in
which the central 6-membered O-ring is open or
substituted by a 5-membered ring, respectively.
However, these four classes of polyphenols are
sometimes generally considered flavonoids as well.
Stilbenoids such as resveratrol, which do not share
with classical flavonoids either a common structure
or a biosynthetic pathway, should not be considered
flavonoids. For the purpose of the present review,
we are considering only “classical” or “true”
*Address correspondence to this author at the Department
of Pharmacology, School of Pharmacy, University of
Granada, 18071 Granada, Spain. Tel: (+34)-958241791,
Fax: (+34)-958248264, Email: jmduarte@ugr.es
flavonoids, i.e. those with a 2-phenyl-4H-chromene
structure. Variants of this structure lead to the main
different flavonoid subclasses (Fig. 1): A) Flavones,
with a ketone group in position 4, B) Flavanones,
with the 4-ketone group plus a reduction of the 2(3)
carbon-carbon double bond, C) Flavonols, with the
4-ketone plus an hydroxylation at position 3, D)
Flavanonoles, with the 4-ketone, the 3-hydroxyl
radical plus the 2(3) double bound reduction, E)
Flavan-3-ols, flavan-4-ols and flavan-3,4-diols with
hydroxyl groups at position 3, 4 or both,
respectively, and F) Anthocyanidins in which the
oxygen is positively charged (flavylium or 2-
phenylchromenylium ion). These basic skeletons
allow a large number of substitutions, mainly with
hydroxyl or methoxyl radicals. They can be further
conjugated with sugars (C- and O-glycosides) and
can dimerize or polymerize, rendering a large variety
of compounds.

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The pharmacology of flavonoids is extremely
complex for several reasons. First, even if we use the
more restrictive concept, the flavonoid class includes
several thousands of different molecules present in
nature. Second, they are seldom administered as pure
compounds but rather as complex mixtures as they are
present in foods, food supplements, medicinal plants or
nutraceuticals. Third, the qualitative and quantitative
composition of the administered products varies largely
depending on plant genetics, crop variability and
industrial processing, storing or cooking procedures.
Fourth, when administered to animals or humans, they
suffer further chemical modifications by gastric pH or
enzymatic metabolism by intestinal secretions, the gut
microbiota, during absorption at the intestinal wall, in
the liver and in other organs and tissues. Fifth, some
compounds show difficulties in crossing biological
barriers, then, they are poorly absorbed, do not access
the target tissues or are rapidly eliminated. Finally,
even considering a single chemical entity, it is likely to
be non-specific, and may interact with a large number
of targets, i.e. enzymes, receptors, transporters or
channels [2]. Therefore, when considering the
biological effects of flavonoids, we have to face a
milieu of compounds, at varying concentrations,
interacting with multiple targets and for the treatment
of multiple diseases.
During the 80s and 90s of the past century, the
antioxidant effect of flavonoids was considered the
main mechanism of action of flavonoids and other
polyphenols. However, in recent years, the role of
modulation of signaling pathways by direct interactions
of flavonoids with multiple protein targets, namely
kinases, has been increasingly recognized [3].
Moreover, the pro-oxidant effect of flavonoids leading
to the activation of antioxidant defense mechanism,
such as nuclear factor E2-related factor 2 (Nrf2), and
the subsequent regulation of the expression of specific
genes is more recently gaining credibility to explain
their beneficial effects on human health [4].
Notably, despite interacting with multiple
targets, flavonoids are surprisingly safe [5]. This may
be explained because flavonoids have been present in
the mammalian diet for several million years and we
have probably evolved specific mechanisms to avoid
their toxicity. What is far
more puzzling is why these compounds synthesized by
plants benefit human health. One possibility is just a
fortuitous coincidence. However, it may also be that
biosynthetic pathways for signaling compounds
originated in a common ancestor of plants and animals
[6] and the structural motifs of these signaling
molecules and their targets have been conserved during
evolution. In addition, the xenohormesis hypothesis
proposes that animals have evolved the ability to sense
signals from stressed plants [7]. The increased
synthesis of polyphenols in plants by multiple
environmental stresses is well known. Thus, when
ingested by animals, polyphenols inform about the
defective status of its environment, such as short food
supply, and prompts the organism to mount a defense
response.
In this paper, we review the recent evidences
about cardiovascular effects that support a beneficial
role of flavonoids on cardiovascular disease (CVD) and
the potential molecular targets involved.
FLAVONOIDS AND THE VASCULATURE
A large number of vasoactive substances are
released by the endothelial cells displaying a
significant role in the regulation of vascular structure
and function under physiological and pathological
conditions [8]. From all endothelial-derived substances,
it is well-known that nitric oxide (NO) plays an
important function in the maintenance of vascular
homeostasis through the modulation of several
processes, such as blood flow, vascular tone, platelet
aggregation and vascular smooth muscle cells
(VSMCs) proliferation control, being considered as an
emerging molecular target for developing therapeutics
strategies for vascular disorders. Disturbance of NO
signaling pathways represents one of the mayor
determinants of endothelial dysfunction, which is
characterized by the reduction of the NO
bioavailability and oxidative stress increase with the
resulting impairment of the endothelium-dependent
vasodilation and a prothrombic and proinflammatory
state of vascular wall [9-11].
Accumulated evidence suggests that flavonoid-
rich diets are associated with an improvement in
vascular health via increased NO bioavailability and
endothelium-dependent vasorelaxation both in
physiological and pathological conditions. However,
the mechanisms by which they may improve
endothelium functions are not fully known. In this
regard, several molecular mechanisms have been
proposed to explain the beneficial effects of flavonoids
and their metabolites on vascular endothelial function
in both animal models and humans (Fig. 2), including
endothelium- and NO-dependent relaxations,

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 3
antioxidant, anti-inflammatory and antiproliferative
properties [12-15].
Most flavonoids display direct vasodilator
activities in isolated arteries even though with a
different potency [16]. Although mechanisms for these
relaxant effects are not completely determined it
appears that all flavonoids do not exert the same
mechanism, particularly regarding the role of
endothelium and NO. In contrast, some flavonoids,
such as the flavonol myricetin or epigallocatechin
gallate (EGCG), may also induce an endothelium-
dependent contractile response via an increase in
cyclooxygenase (COX)-derived vasoconstrictor
prostanoids [17-19].
An endothelium-independent vasodilation
mechanism has been described for some flavonoids
such as quercetin and kaempferol in isolated arteries,
which may be at least partly responsible for the
decrease in arterial pressure in some experimental
models [16, 20-22]. Interestingly, these direct
vasodilator effects of flavonoids are more potent in
coronary and resistance arteries than in conductance
vessels [23, 24]. Part of these endothelium-independent
relaxant responses can be attributed to an activation of
KATP channels, a decrease of Ca2+ influx into VSMCs
by blocking Ca2+ channels and an inhibition of the
intracellular Ca2+ release from the endoplasmic
reticulum (ER) [25, 26].
On the other hand, the improvement of
endothelial dysfunction associated with several CVD
induced by flavonoids seems to be related to an
increase on endothelium- and NO-dependent
relaxations. Flavonoids may induce an acute
endothelium-dependent vasodilation by raising
endothelium-derived relaxing factors through increased
NO and H2O2 release. This effect does not appear to be
related to a protective effect on NO but rather to a pro-
oxidant mechanism involving the endothelial release of
reactive oxygen species (ROS) because it can be
inhibited by superoxide dismutase (SOD) and catalase
(CAT) [21, 27-30]. Nevertheless, the main mechanism
involved in the endothelium-dependent vasodilation
induce by flavonoids is related to NO availability in the
vasculature. Flavonoids may regulate NO production
by increasing endothelial nitric oxide synthase (eNOS)
expression and activity, as well as reducing degradation
of NO [14, 15]. Several flavonoids such as red wine
polyphenols (RWPs) and delphinidin have shown
enhanced eNOS mRNA expression in endothelial cells
[31-33]. Moreover, eNOS activity may be modulated
by flavonoids through a Ca2+/calmodulin-dependent
pathway by increasing in the intracellular Ca2+ levels
[33-36], or through a Ca2+-independent mechanism by
phosphatidylinositol 3-kinase (PI3-K)/ protein kinase B
(Akt)-dependent eNOS phosphorylation at the
activation site Ser1177 and dephosphorylation at the
inhibition site Thr495 [30, 37-39]. This latter
mechanism seems to involve a pro-oxidant effect of
flavonoids because it is prevented by permeant
analogues of SOD [40-42]. Controversially, most
isolated flavonols such as quercetin failed to increase
eNOS expression and endothelial NO production in in
vitro studies, showing conflicting results depending on
the conditions of oxidative stress [32, 43, 44]. Thus, in
the absence of oxidative stress, quercetin may scavenge
NO by its auto-oxidation in aqueous solutions
generating O2-, which ultimately inactivates NO [43].
Furthermore, quercetin reduced eNOS expression in
tumor necrosis factor alpha (TNF-α) stimulated
endothelial cells [45] and normalized the upregulation
of eNOS observed in aorta from spontaneously
hypertensive rats (SHR) [46]. Besides, we described
that chronic treatment with quercetin was unable to
improve the endothelium-dependent relaxation to
insulin in aortic rings from normotensive and
hypertensive animals being this effect related to a
direct inhibitory effect of quercetin on PI3-K/Akt-
dependent eNOS phosphorylation [47]. In contrast,
under increased oxidative stress conditions in which
NO metabolism is accelerated, quercetin can improve
the impaired endothelial-dependent vasodilatation due
to its antioxidant properties suggesting that the increase
in NO-dependent vasodilatation induced by quercetin is
due to a reduced O2--driven NO inactivation more than
from a direct effect on NO production [48, 49].
Moreover, flavonoids may also increase NO production
in endothelial cells by down-regulation of caveolin-1
(Cav-1) expression, an important negative regulator of
eNOS activity in endothelial cells, via activation of
extracellular-signal-regulated kinases 1/2 (ERK1/2)
and inhibition of p38 mitogen-activated protein kinase
(p38MAPK) signaling [50-52]. Besides, NO activity and
endothelium-dependent relaxation are strongly
dependent on phosphodiesterases (PDE) activity.
Several flavonoids have also been reported to inhibit
several PDE isoforms [53]. In fact, some flavonoids,
such as kaempferol, potentiate the relaxant response to
the soluble guanylyl cyclase (sGC) activator sodium
nitroprusside [16]. Thus, inhibition of PDEs may
represent another potential mechanism for flavonoid-
induced prevention of endothelial dysfunction.
Furthermore, increase endothelial-dependent
vasodilatation induced by some flavonoids, such as the
flavonol quercetin, may occur as a consequence of the

4 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
inhibition in the release of endothelium-derived
vasoconstrictor prostanoids [54, 55].
On the other hand, flavonoids also display
vasodilatory activities by reducing degradation of NO
through indirect pathways that may negatively affect
NO availability in the vasculature including O2--
scavenging activity, decrease of endogenous inhibitors
of eNOS such as asymmetrical dimethylarginine
(ADMA), blockade of vasoconstrictors release such as
endothelin-1 (ET-1) and angiotensin-II (AngII), and
inhibition of several enzymes involved in the O2--
driven NO inactivation such as NADPH oxidase,
acetylcholinesterase and angiotensin-converting-
enzyme (ACE) [49, 56-60].
Flavonoids are known to be potent free radical
scavengers derived from their specific chemical
structural features such as the number and position of
functional groups, mainly hydroxyl (OH) groups,
conjugation groups or the degree of glycosylation in
the ring structure of flavonoids [61-63]. Although this
effect is shared with some of their metabolites, the
antioxidant capacity tends to be lower because the
radical-scavenging OH groups are blocked by
methylation, sulfation and glucuronidation [20, 64, 65].
By scavenging free radical, flavonoids not only protect
NO from O2--driven inactivation but also prevent the
formation of ONOO- and related nitrotyrosine
formation, which may represent one mechanism by
which flavonoids may exert their beneficial actions in
vivo [65-68]. Moreover, they are powerful inhibitors of
low density lipoproteins (LDL) oxidation, a key event
in the process of atherosclerotic plaque genesis [69].
Additionally, flavonoids exert pro-oxidant metals
chelating properties, thereby reducing the rate of
Fenton reactions and the formation of highly DNA-
damaging -OH radicals [61, 62, 70, 71]. Independently
from their ROS scavenging effects, and probably more
importantly, flavonoids can modulate NO
bioavailability through the inhibition of multiple ROS
generating enzymes including 5-lipooxygenase, COX,
xanthine oxidase and NADPH oxidase [46, 72-75], and
the potentiation of antioxidant enzymes such as SOD,
CAT, and peroxidase [76]. Moreover, due to their
antioxidant properties, flavonoids may also prevent
tetrahydrobiopterin (BH4) oxidation and eNOS
uncoupling, process in which eNOS becoming a
dysfunctional O2--generating enzyme [49].
Furthermore, recent studies have suggested that
flavonoids are able to improve endothelial function
under hypertensive [77] and hyperglycaemic [78, 79]
conditions through the attenuation of ER stress by
reducing ROS production and by attenuating ER stress
downstream signaling pathways owing to their
antioxidant properties. However, more studies are
necessary to confirm the protective effects of
flavonoids against endothelial ER stress-associated
oxidative stress on vascular dysfunction.
Additionally, flavonoids may also decrease the
synthesis and release of vasoconstrictor mediators
including AngII, ET-1 and prostaglandins. Both AngII
and ET-1 are two potent stimuli for the induction of
NADPH oxidase, a major source of oxidative stress in
the vascular wall. Flavonoids may interfere with the
synthesis of AngII by interfering with ACE activity
[56] or with its signalling pathways [48]. It has also
been described that flavonoids such as quercetin and
epicatechin may decrease ET-1 production both in vitro
and in vivo studies by suppressing transcription of the
ET-1 gene via Akt-regulation [49, 80-82].
Other molecular targets involved in the
protective effects of flavonoids on vascular endothelial
function are arginase-2, Nrf2 and sirtuin 1 (SIRT-1).
Some flavonoids may reduce the activity of arginase-2,
which is an enzyme that competes with eNOS for L-
arginine, thereby preventing the inhibition of NO
formation [83]. Nrf2 is a transcription factor that
regulates the expression of numerous ROS detoxifying
and antioxidant genes. Upon activation, the kelch-like
ECH-associated protein 1 (Keap-1)/Nrf2 complex is
dissociated, and Nrf2 translocates to the nucleus, where
it binds to antioxidant response elements (ARE),
triggering the transcription of antioxidant defense
enzymes, including NADPH:quinone oxidoreductase 1
(NQO1), heme oxygenase-1 (HO1), glutathione-S-
transferase (GST) and γ-glutamylcysteine ligase
(GCL). Several flavonoids, such as the flavonol
quercetin or the flavanols EGCG and epicatechin, may
activate the Nrf2/ARE pathway in the vascular wall
leading to increase the expression of antioxidant
enzymes [84-87]. SIRT-1 binds directly to eNOS and
enhances its activity by deacetylation of eNOS at
Lys496 and Lys506, thereby stimulating NO
production and promoting vascular relaxation [88].
Down-regulation or pharmacological inhibition of
SIRT-1 is highly associated with endothelial
dysfunction [89-92]. Recent studies have shown that
quercetin, one of the most abundant and widely
distributed flavonoids in nature, might be a SIRT-1
activator and consequently improve the impaired
endothelial function [93, 94].
Also noteworthy is that flavonoids exert anti-
inflammatory and anti-proliferative activities in the
vasculature, which may also account for their
antihypertensive and antiatherosclerotic effects.

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 5
Vascular inflammation is a complex biological process
that involves the overproduction of several pro-
inflammatory mediators and vascular adhesion
molecules through the activation of different signaling
pathways, including the nuclear factor kappa-light-
chain-enhancer of activated B cells (NF-kB) pathway.
Activation of NF-kB plays a crucial role in the
expression of pro-inflammatory mediators, including
inducible nitric oxide synthase (iNOS), COX-2, TNF-α
and interleukin-6 (IL-6). Moreover, activation of the
NF-κB signaling pathway is closely related to the
activation of mitogen-activated protein kinases
(MAPKs) that are involved in intracellular signaling
pathways during pro-inflammatory responses
associated with endothelial dysfunction. Several studies
have shown that flavonoids may promote their anti-
inflammatory properties through the inhibition of the
redox-sensitive NF-kB/MAPKs signaling pathway [90,
95-99]. In addition, flavonoids may also inhibit
endothelial proliferation and migration and tube
formation [44, 100, 101]. This effect is associated with
decreased vascular endothelial grown factor (VEGF)
expression and might result in reduced angiogenesis in
vivo [102-104]. Therefore, several studies have shown
that flavonoids inhibit proliferation and hypertrophy or
induce apoptosis in vascular smooth muscle cells in
culture. The inhibitory effects of flavonoids on
hypertrophy and DNA synthesis of vascular smooth
muscle cells appear to be related to reduce MAPKs
activity [105-108].
Although a moderate consumption of
flavonoid-rich foods represents a promising tool for
increasing the NO bioavailability against vascular
disorders, one of the mayor drawbacks for their employ
in the clinical practice is their low bioavailability in
vivo due to they are poorly absorbed and rapidly
metabolized and degraded. In this regard, several
clinical studies have reported that when flavonoids are
orally administered, their plasmatic concentrations are
very low when compared with the concentrations
employed during in vivo and in vitro experiments and
appears not to be sufficient to ensure protective effects
on vascular endothelial function [109-112]. Thus, the
mayor drawback in the lack of beneficial effects of
flavonoids in human seems to be related to their low
bioavailability as a consequence of their widely
metabolism and the influence of the gut microbiota in
their absorption [74, 112, 113]. Other limitations of the
currently available clinical trials are the complex
flavonoid-rich diets composition which makes it very
difficult to identify the specific compound responsible
for the protective effects, the patients’ genotypic
profile, the relative short duration of the therapy and
the timing of the initiation of antioxidant therapy [114-
118]. In addition, accumulated evidence suggests that
acute but not chronic consumption of flavonoid-rich
foods have an impact on vascular function outcomes
[119-122]. Therefore, further longer duration studies
using pure flavonoids are required to confirm their
protective effects in NO-mediated vascular relaxation
in healthy humans and patients with endothelial
dysfunction.
FLAVONOIDS AND PLATELETS
Increased platelet adhesion and activation play
an important role in the pathogenesis of CVD [81, 123-
126]. Recent literature emphasizes the potential platelet
antiaggregant effects of flavonoids, suggesting that
they could be used as therapeutic agents against CVD
driven by platelet hyperactivity [127-130]. Several
molecular mechanisms have been proposed to be
involved in the antiplatelet properties of flavonoids
(Fig. 3) including: i) the inhibition of thromboxane A2
(TxA2) formation by blocking the arachidonic acid
(AA) pathway [131], ii) the suppression of intracellular
mobilization of Ca2+ from the ER by blocking calcium
channels [132], iii) the increase of cyclic nucleotides
through the inhibition of PDEs [126, 133, 134], and iv)
the blockage of the signaling pathways initiated by
ADP [135], thrombin [136], collagen [137], fibrinogen
[138] or TxA2 receptors activation [139]. Other
mechanisms may also be involved such as a reduction
of the oxidative burst and the prevention of a decrease
in NO production owing to their antioxidant properties
and their capacity to increase NO production in
platelets, respectively [140-143]. Furthermore,
flavonoids may also inhibit the expression of
endothelial adhesion molecules such as vascular cell
adhesive molecule-1 (VCAM-1), intercellular adhesive
molecule (ICAM-1) and E-selectin, and exert an anti-
inflammatory activity by decreasing production of pro-
inflammatory mediators such as TNF-α, IL-6 and C-
reactive protein, thereby preventing the recruitment of
inflammatory cells and the formation of platelet-
leukocyte aggregates into the subendothelial space
[128, 144, 145].
Finally, while in vitro and ex vivo data are
consistent, clinical trials on the antiplatelet effects of
flavonoids are limited and provide conflicting results
[120, 146-149]. Unlike the in vitro and ex vivo studies,
in most of clinical trials the number of patients is
insufficient and the beneficial antiplatelet effects of
flavonoids depend on the presence of high number of
variables such as the health condition of subjects, the

6 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
large number of different flavonoids in the natural
extracts administrated and their limited bioavailability
caused by the complex metabolism to which they are
subjected to in the organism, suggesting that only
cautious conclusions may be drawn from studies on
flavonoids. Thus, further well-controlled clinical trials
are required to go in depth into the molecular
mechanisms, bioavailability, therapeutic doses and
toxicity of these flavonoid-rich diets on platelet
function to develop better strategies to treat
cardiovascular diseases.
FLAVONOIDS AND HYPERTENSION
High blood pressure (BP) is one of the most
relevant independent risk factors for cardiovascular
events, including coronary heart disease and stroke.
Indeed, hypertension is the leading preventable risk
factor for premature death and disability worldwide
[150]. The majority of hypertension cases is considered
essential hypertension because they have no known
etiology [151]. Essential hypertension is a
multifactorial and multigenic disorder, which means
that various mechanisms contribute to a greater or
lesser extent to increase BP. Despite the large number
of antihypertensive drugs available, in many patients
BP still remains not optimally controlled and persists at
high risk of cardiovascular complications [152].
Therefore, efforts to reduce the prevalence of
hypertension have focused on non-pharmacologic
approaches. Among the wide-ranging lifestyle
modifications, dietary measures are one of the most
effective adjustments for the management of arterial
hypertension and an increase in fruit and vegetable
intake is included in the guidelines for modulating
hypertension [153, 154]. Beyond the well-known
effects on BP of the Dietary Approaches to Stop
Hypertension (DASH) [155] and the Mediterranean
diet [156], flavonoids, flavonoid-containing dietary
supplements and nutraceuticals have garnered
significant attention for their BP lowering properties.
The positive effect of flavonoid-rich foods on
hypertension has been documented in many
experimental and human studies. Observational studies,
clinical trials and meta-analysis suggest a reduction in
BP after intake of flavonoid-containing foods:
vegetables and fruit-rich diet [157, 158] fruit juices
[159], berries [160, 161], green and black tea [162-167]
and cocoa and dark chocolate [168-172] are some
examples. Cocoa may be superior to other sources of
flavonoids in reducing BP. Current data suggest that
increases in NO bioavailability, anti-inflammatory and
antioxidant effects may be central mechanisms by
which flavonoid-rich foods can alleviate hypertension
[173]. When products enriched with flavonoids or
flavonoid extracts have been administered similar
antihypertensive results have been described in pre-
clinical and clinical studies [165, 174-178].
Nevertheless, in strong contrast, additional trials have
been published with conflicting results, particularly
with regard to soy, red wine, chocolate and tea [122,
178-182]. This may be due in part of the variability in
study designs, heterogeneity between participants and
because of the dosage, the wide variability in the
flavonoid content and their bioavailability and the
presence of alcohol or high calorie (sugar and saturated
fat) and caffeine content in some of these products.
These differences highlight the need to study the
individual purified flavonoids.
In their systematic review, Clark et al.[112]
summarize the ability to reduce or to attenuate a rise in
BP in the principal dietary flavonoids of the five
subgroups more commonly consumed: flavonols
(quercetin, kaempferol and myricetin), flavanols
(catechin and epicatechin), flavanones (luteolin,
apigenin and chrysin), flavanones (naringin and
hesperidin) and anthocyanins. Although all of them
have demonstrated antihypertensive effects in different
animal models and some clinical studies, of these
single flavonoids that have come under investigation
we will discuss quercetin and epicatechin because they
have shown the most consistent ability to reduce BP.
Quercetin has demonstrated antihypertensive
effects in the most common preclinical models of
hypertension. The first report on the antihypertensive
effects of quercetin was carried out on SHR, an
experimental model that mimics human hypertension
[183]. Since then, these results in SHR have been
confirmed and extended by others [46, 47, 184-186].
Furthermore the BP-reducing effect of such a flavonoid
has been extensively studied in many different rodent
models of hypertension: two-kidney one-clip Goldblatt
rats [55], rats with aorta constriction [187], Nω-nitro-
L-arginine methyl ester (L-NAME)-treated rats [54],
infused with AngII [188], deoxycorticosterone acetate
(DOCA)-salt hypertensive rats [189], Dahl salt-
sensitive hypertensive rats [190, 191], and NaCl-
induced hypertension [192]. The effects of quercetin on
the elevated BP have been demonstrated also in
metabolic syndrome models such as obese Zucker rats
[193] or administrating a high-fat and high-sucrose diet
[194]. The chronic dose most frequently used in these
studies has been 10 mg/Kg per day, but the effective
doses used range from 2 to 300 mg/Kg per day [195].

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 7
In humans, epidemiological studies have found
an inverse relationship between dietary quercetin intake
and hypertension. Several clinical trials have
demonstrated a reduction in BP after the administration
of pure quercetin. The study of Edwards et al. [196]
exhibited BP-lowering effects of quercetin
supplementation in patients with stage 1 hypertension
without reduction in systemic markers of oxidative
stress. Egert et al. demonstrated that quercetin reduces
BP in overweight subjects with a high-CVD risk
phenotype [197] and in overweight-obese carriers of
the apo epsilon3/epsilon3 genotype but not in carriers
of the epsilon4 allele [198]. Lee et al. [199]
investigated the effects of quercetin on cardiometabolic
risks in healthy male smokers. In the quercetin-rich
supplementation group, systolic and diastolic BP
decreased significantly. Larson et al. [29] conducted
another double-blind, placebo-controlled, crossover
design using acute quercetin aglycone. The
administration of this flavonoid reduced BP in stage 1
hypertensive men, but did not change ACE activity, ET-
1 levels, or NO bioavailability and no changes in
vascular reactivity were observed. These results are
interesting because all of them are considered principal
mechanism to reduce BP. In addition, quercetin intake
has proved to reduced systolic BP in women with type
2 diabetes [200]. However, not always has been
observed this beneficial effect. In some studies,
quercetin has not been able to lower BP in hypertensive
subjects [201, 202]. Recently, a meta-analysis has been
published summarizing seven of these randomized
placebo-controlled clinical trials and showing a
significant effect of quercetin supplementation in the
reduction of BP, possibly limited to, or greater with
dosages of >500mg/day, amounts higher than
consumed in the general public [203]. Indeed,
Vogiatzoglou et al. [204] have shown that the habitual
intake of flavonoids in Europe is lower that the dosage
found to have a significant health effect.
Pérez et al. [205] have demonstrated that
quercetin exerted a vasodilator effect on young healthy
human arteries, but this diameter increase in a large
conduit artery was not associated with changes in BP.
This fact is important to the prevention of hypertension
in normotensive individuals, because it hasn´t been
observed a reduction in BP in normal controls in
preclinical [46, 206] and clinical studies [196, 199,
207-209]. Therefore, to exert a BP-lowering effect of
quercetin a certain degree of high BP may be required
[12, 196].
Several potential mechanisms are supposed to
be responsible for the positive effect of quercetin;
among them, the antihypertensive effect of quercetin
has been attributed to its ability to ameliorate
endothelial dysfunction [197] by activation of eNOS,
increased bioavailability of NO [192], a direct
vasodilator action [24, 210] as well as antioxidant and
anti-inflammatory properties [46]. Direct renal
protection might also play some role in the BP-
lowering effect of this flavonoid [190, 191]. However,
it is unclear whether the in vivo antihypertensive effects
are due to quercetin itself or its metabolites [195]. In
addition, we have already mentioned that some authors
have obtained controversial results [29] and they
suggest that the mechanisms responsible for the BP
lowering effect of quercetin remain unknown.
Epicatechin (present at high concentration in
apples, grapes, tea and cocoa) seems to be a major
bioactive flavanol. Several polyphenolic extracts
containing mainly flavanols (cocoa extract, black or
green tea and red wine polyphenols) decreased BP in
rat models of experimental hypertension [174, 211-
214]. Animal studies using purified epicatechin have
reported antihypertensive effects as well. The effective
doses used of epicatechin range from 10 to 350 mg/Kg
per day. Doses below 5 mg/kg per day appear to have
no antihypertensive effect [215, 216]. Gómez-Guzmán
et al. [215] observed that epicatechin reduces BP and
improves endothelium-dependent vasorelaxation in
adult DOCA-salt rats. The BP-reducing effect of
epicatechin has been shown in other models of
hypertension such as SHR, which is considered to
resemble human essential hypertension [217, 218], and
fructose-induced [219]. The administration of isolated
epicatechin in L-NAME-induced animal model has
been analyzed in different studies. In the study of
Litterio et al. [220] animals received L-NAME for 4
days and epicatechin was able to prevent the increase
in BP, oxidative stress and restored NO bioavailability.
However, in the study conducted by Gómez-Guzmán et
al. [221], chronic epicatechin treatment (4 weeks)
reduced oxidative stress and proinflammatory status,
but did not modify the development of hypertension,
demonstrating the duration, the dose and disease-
dependent effect of epicatechin, and the key role of NO
in the antihypertensive effects of this flavanol.
Piotrkowski et al. [222] analyzed the effects of this
flavanol in the heart of Sprague-Dawley rats treated
with L-NAME. The redox status in cardiac tissue was
improved by epicatechin administration: restored NO
steady state levels through effects on both, its synthesis
and degradation via the reaction with O2-.
Therefore epicatechin resulted able to decrease
oxidative stress and inflammatory status (reducing

8 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
ROS and pro-inflammatory markers and raising
antioxidant enzymes) [215, 221, 222], inhibit ACE
activity, reduce plasma ET-1 and COX-2 levels [75,
223, 224], improve endothelial function (via improved
vascular NO bioavailability) [81, 215, 218, 220, 224],
and modulate cell signaling (pathways mediated by Src
dependent activation of PI3-K, phosphorylation of Akt
and ERK1/2 inhibition, for instance) [56, 215, 221].
The antihypertensive effect of epicatechin is said to be
due to these effects.
There is a large body of evidence that supports
the cardiovascular beneficial effects of products
containing or enriched with epicatechin in human
studies [159, 170, 178, 225-228]. Nevertheless, the
properties of pure epicatechin have not been
consistently studied in humans. Although some clinical
studies have evaluated the beneficial properties of
epicatechin [122, 223, 229] more clinical studies
should be considered in order to provide conclusions
about the benefits of epicatechin as antihypertensive
compound.
Dietary flavonoids are a large and diverse
range of polyphenolic compounds. Indeed, the
mechanism by which flavonoids mediate the BP
lowering effect remain elusive and it is complicated to
resume due to the structural diversity of the subgroups.
For instance, inhibition of ACE activity appears to be
important in epicatechin antihypertensive effects [230]
but quercetin had no effect on ACE activity [29, 56].
However, a variety of mechanisms have been proposed.
In general, the potential antihypertensive benefits of
flavonoids are suggested to be due to chemically
interact with ROS, and multiple changes in a variety of
enzymes, ion channels and transcription factors [195].
A potential and important mechanism that
might contribute to the lowering of BP of flavonoids is
to improve endothelial function (mentioned above). A
reduction in ROS it is considered another extended
hypothesis to reduce hypertension by flavonoids. The
most plausible explanation could be a direct O2-
scavenger effect or by inhibition of O2- generating
enzymes and reducing oxidative stress [183]. The
lowering of BP may be attributed to direct renal effects
as another mechanism of antihypertensive action of
flavonoids [54, 189-191].
In summary, the evidence presented in the
current literature shows that a majority of the
flavonoids studied (especially quercetin and
epicatechin) have demonstrated antihypertensive effect
in animal and human studies, but only when high BP is
present. Therefore, the results observed suggest that
flavonoids might be considered as an add-on to
antihypertensive therapy. However, further studies are
necessary to elucidate the mechanisms responsible for
the BP lowering effect and to investigate the clinical
relevance of each one of these compounds.
FLAVONOIDS AND ATHEROSCLEROSIS
Under some circumstances, vessel walls can
start to fill up and thicken due to the accumulation of
blood-carried or even vessel-wall produced substances,
such as cholesterol, fatty acids, calcium, fibrin and
cells such as red blood cells, platelets, smooth muscle
cells, fibroblasts and macrophages. This process, called
arteriosclerosis, hardens, stiffens and narrows the
vessel where it occurs, decreasing the supply of blood
reaching the tissue. When, due to obesity, an unhealthy
diet or a lipid metabolism problem, cholesterol and
fatty substances (such as triglycerides and LDL), but
also fibrin, calcium and extracellular matrix
components, accumulate into the vessel wall,
macrophages infiltrate and phagocyte the oxidized-
LDL (ox-LDL) due to high levels of oxidative stress,
becoming “foam cells”, so-called because of their
appearance due to the droplets of fat inside them. The
infiltrate forms the typical fatty streaks in
atherosclerotic vessels. This complex mixture of
substances from the blood and vessels, together with
the infiltrated vascular cells is named “plaque”, which
completely alters the vessel wall, making it harder and
narrower, resulting in a particular type of
arteriosclerosis called atherosclerosis. With time,
plaque can evolve to become so big as to create a
thrombus able to obstruct the vessel and produce tissue
ischemia. Or, on the other hand, it can become
unstable, rupture and release a fragment, and emboli,
which could cause an embolism clogging a vessel
anywhere in the body. Thus, atherosclerosis is a
chronic disease, developed silently during many years
until its sudden clinical manifestations appear which
are ischemic heart disease, stroke and peripheral
arterial disease.
Chronic inflammation, oxidative stress, high
blood cholesterol and lipid levels, obesity, smoking,
increasing age, hypertension, family history,
endothelial dysfunction, an unhealthy diet, insulin
resistance and diabetes are known risk factors for
atherosclerosis [231, 232]. Although mortality derived
from ischemic heart disease or stroke has clearly
declined since the 90’s in developed countries,
ischemic heart disease is still the main cause of
premature adult mortality [233]. Therefore,
atherosclerosis is the most common, worldwide spread

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 9
and, hence, the most dangerous form of arteriosclerosis
[233, 234]
As it has been mentioned above, in the onset
and development of atherosclerosis there are many
processes involved. Flavonoids are endowed with
multiple and diverse mechanisms of action such as
enzyme inhibition and activation, modulation of gene
and protein expression, antioxidant, antimicrobial,
antiviral, anti-ulcerogenic, cytotoxic, anti-neoplastic,
mutagenic, antihepatotoxic, antihypertensive,
hypolipidemic, antiplatelet and anti-inflammatory
activities [235]. Because of these actions, flavonoids
are able to affect the course of the disease and prevent
or reduce it, either in vitro, in vivo or even as observed
in clinical trials.
Years ago, there were doubts about the benefits
of flavonoid intake to prevent atherosclerosis, because
of some contradictory results, different doses utilized in
the studies and lack of in vivo data [236]. Nowadays,
we still suffer some of these problems, such as non-
standardization of compounds and doses, and the need
of more clinical studies with single flavonoids, but the
accumulated results have left obsolete this ancient
discussion. It has been clearly demonstrated that
several flavonoids are able to prevent and attenuate
atherosclerosis both in vitro and also in vivo in animal
models. For instance, quercetin, the most studied
flavonoid, has been able to protect from the
progression of atherosclerosis in a study recently
published. In apolipoprotein E deficient (ApoE-/-) mice,
one of the most common animal models to study
atherosclerosis, the administration of an AIN-93G diet
for 20 weeks supplemented with 0.1% (w/w) quercetin,
inhibited dendritic cell activation, inflammatory
response and, more importantly, inhibited the
progression of the atherosclerotic disease otherwise
observed in the non-treated mice. Moreover, the
treatment resulted in a significant reduction of the
atherosclerotic lesion in the aortae by 30% [237]. In a
later in vitro study, these effects were attributed to the
downregulation by quercetin of dendritic cell activation
via increased disabled 2 (Dab2) protein expression
which, in turns, downregulated the essential NF-κB
inflammatory pathway. The O-methylated flavone
nobilentin was also able to inhibit NF-κB inflammatory
pathway in human umbilical endothelial cells
(HUVECs) and therefore, could possess
antiatherogenic effects [238]. Previous studies had
already shown that quercetin was more effective than
other flavonoids in slowing down the progression of
atherosclerosis and reducing plaque size, and that the
observed effects were due to a reduction in the
inflammatory status (decreased levels of vascular O2-
and leukotriene B4, aortic F2-isoprostane and plasma-
sP-selectin), the improvement of the endothelial
function (augmented vascular eNOS activity) and the
oxidative stress status (increased HO-1 protein and
nitrate excretion). Although less effective, the dimeric
catechin theaflavin was also able to reduce
atherosclerotic lesion size and improve some of these
parameters in the same study [81]. Nonetheless, these
are not the only clear results proving the
antiatherogenic properties of quercetin in vivo. Also
using the same model of ApoE-/- mice, but this time
feed a high fat diet (HFD) for 24 weeks, the
supplementation of the diet with quercetin (25, 50 or
100 mg/kg for the low, middle or high doses,
respectively), reduced the area of the atherosclerotic
plaque in aorta, curiously by 27.7% with the high dose
of quercetin, very close to the 30% reduction observed
in the above mentioned study. This treatment also
decreased macrophage infiltration into the
atherosclerotic lesion and ox-LDL accumulation in a
dose dependent manner, reduced whole-body oxidative
stress and inhibited the aortic expression of NADPH
oxidase subunits p47phox and p67phox when compared to
non-treated mice. Moreover, when continued this
research in vitro, quercetin was also able to inhibit the
translocation of p47phox to the cell membrane and also
reduce NADPH oxidase activation by ox-LDL in
mouse peritoneal macrophages [239]. It is interesting to
note that apart from the systemic antiatherogenic
properties of quercetin, quercetin glucuronides, such as
quercetin-3-glucuronide (Q3GA), the main quercetin
metabolite found in human blood, specifically
accumulates in atherosclerotic lesions in human aorta,
mainly in the foam cells derived from macrophages
[240]. These metabolites are also active when
deconjugated and turned into quercetin aglycone again
[205]. In a recent meta-analysis, flavonols, such as
quercetin and its metabolites, have proven to be the
most effective, among 18 flavonoids tested, to reduce
aortic atherosclerotic lesions in the model of the
ApoE-/-mice [241].
Other flavonoids have been less extensively
studied than quercetin, but have also shown clear anti-
atherosclerotic properties, mainly due to their abilities
to inhibit several pro-inflammatory mediators and
pathways. Thus, dihydromyricetin also possess
antiatherogenic properties as shown in the
atherosclerotic model of HFD feed-LDL /receptor
deficient (LDLr-/-) mice. It was due to its capabilities,
similar to those of quercetin, to inhibit the formation of
macrophage-derived foam cells, reduce oxidative

10 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
stress, ox-LDL formation and inflammatory markers,
improve endothelial function and reduce the increased
serum lipid levels [242]. In an interesting study about
the effects of dyslipidemia in cerebral arteries structure
and flow, catechin prevented the changes on vessel
wall structure and compliance in atherosclerotic
LDLr−/−:hApoB-100+/+ mice. It was attributed to a
reduction in oxidative stress-derived ROS,
normalization of pro-metalloproteinase-9 (MMP-9)
activity and improvement of the endothelial function
[243]. Similar actions are shared by other flavonoids,
mainly differing in their degree of activity and
therefore making some more useful against
atherosclerosis than others, as has already been shown
[81]. According to this, dietary supplementation of
luteolin (0.6% w/w for 3 weeks) to male C57BL/6 mice
was able to reduce TNF-α-induced vascular
inflammation. Thus, it: decreased serum levels of
chemokines such as the mouse homolog of human
monocyte chemotactic protein-1 (MCP-1), IL-8 and
ICAM-1; inhibited adhesion of monocytes to the
endothelium (an essential step for the later formation of
foam cells in the atherosclerotic plaque); reduced
VCAM-1 and monocyte-derived macrophages in the
aorta when compared to non-treated mice. In vitro,
luteolin had similar results inhibiting TNF-α-induced
adhesion of monocytes to a stable line of HUVECs
(EA.hy 926 cells) probably by suppressing TNF-α-
stimulated expression of MCP-1 and adhesion
molecules ICAM-1 and VCAM-1. Interestingly, the
complex anti-inflammatory effects of luteolin seemed
to be mediated by the inhibition of the NF-κB pathway
as the flavonoid inhibited TNF-α-induced NF-κB
activity and other processes related to its function
[244]. The flavonoid naringenin has also shown to
inhibit macrophage infiltration in adipose tissue when
tested in a short treatment (14 days) at a dose of 100
mg/kg/day in high-fat feed mice. This effect was, as for
luteolin, related to the inhibition of MCP-1. Naringenin
however, did not improve body weight, blood glucose
or lipid profile when compared to non-treated high-fat
feed mice [245]. Also baicalin (at a dose of 100
mg/kg/day for 12 weeks), proved to inhibit MCP-1,
together with VCAM-1 and IL-6, in kidneys of high-
cholesterol feed ApoE-/- mice, protecting therefore their
renal function [246]. The important role of flavonoids
preventing ox-LDL damage to the endothelium was
shown in a study where pretreatment with EGCG
proved to protect HUVECs from ox-LDL-induced
oxidative damage increasing eNOS expression and
improving endothelial function, preventing iNOS
induction and decreasing NADPH oxidase subunits
expression. Moreover, EGCG pretreatment reversed
ox-LDL alteration of the Jagged-1/Notch pathway,
being this action, according to the results, the ultimate
responsible for the protective effects observed [247].
Apart from the already mentioned effects of
flavonoids protecting LDL from oxidation and
therefore the appearance of foam cells, they can also
promote the efflux of cholesterol from the
macrophages, thus reducing as well the formation of
foam cells. This was demonstrated with the treatment
of RAW264.7 macrophages with chrysin. The
flavonoid increased high density lipoproteins (HDL)-
mediated cholesterol efflux and reduced cholesterol
level in a dose dependent way in these cultured
macrophages. Moreover, it inhibited ox-LDL uptake by
macrophages, increased mRNA levels of peroxisome
proliferator-activated receptor gamma (PPARγ) and its
transcriptional activity. It is noteworthy that chrysin
effectiveness reducing intracellular cholesterol was
comparable with that of the hypocholesterolemic drug
lovastatin [248]. The effects of flavonoids on reverse
cholesterol transport are currently a field of great
therapeutic interest to prevent and to treat
atherosclerosis [249].
A recently described mechanism by which
some flavonoids seem to act is by increasing the
activity or expression of paraoxonase (PON) proteins.
PONs are enzymes which have been related with anti-
inflammatory, anti-oxidative, antiatherogenic
properties [250]. Studies have shown that quercetin and
also isorhamnetin are able to increase PON2 gene
expression in cultured mice macrophages. However,
quercetin was ineffective in humans, probably due to
glucuronic acid conjugation, which decreased PON2
inducing activity, clearly showing again the different
effects of flavonoids and their metabolites [251]. Very
similar results were obtained when investigating
quercetin effects on PON1 gene expression and activity
[252]. Quercetin also showed anti-atherosclerotic
properties improving PON1 activity, protecting LDL
from oxidation and reducing lipid peroxidation in a rat
model of oxidative damage with mercuric chloride
[253]. Catechin had similar, although less powerful,
effects. More recent studies, although using extracts
and enriched foods, have been performed deepen in the
effects of flavonoids on PON activity in humans. These
studies have confirmed an increase in PON activity or
expression thanks to these compounds [254, 255].
MicroRNAs (miRNAs) are a recent and
promising field of research for CVD. miRNAs are
small pieces of non-coding RNAs, which are able to
regulate the expression of certain genes and therefore

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 11
regulate protein expression. It has been shown that
numerous miRNAs play a role in the vascular system
modulating several processes, from monocyte adhesion
to endothelial cells to vascular inflammation or
adhesion molecules expression [256] and moreover are
altered in some pathologic stated such as hypertension,
atherosclerosis and diabetes [257]. Thus, it has been
demonstrated that chronic administration of
proanthocyanidins (from a grape seed
proanthocyanidin extract) at a dose of 25 mg/kg/day for
3 weeks, reversed the increased levels of miR-33a and
miR-122, important regulators of lipid metabolism in
the liver, in dyslipidemic obese rats [258]. Quercetin
and isorhamnetin were also able to downregulate the
proinflammatory miR-155, an inflammatory response
modulator, in RAW264.7 macrophages stimulated with
lipopolysaccharide (LPS) [259]. However, the
metabolite Q3GA was not. An interesting study linked
two of the newest discovered anti-atherosclerotic
mechanisms of flavonoids, gut microbiota activity
modulation and miRNAs activity: protocatechuic acid
is a metabolite of the anthocyanin cyanidin-3 to 0-β-
glucoside, formed by the action of gut microbiota. It
has been reported to exert antiatherogenic effects in
ApoE-/- mice, reverting cholesterol transport and
promoting its efflux from macrophages, as chrysin also
did [248]. However, protocatechuic acid achieved its
effect downregulating miR-10b, which in turns
inhibited ATP-binding cassette transporter A1
(ABCA1) and G1 (ABCG1), essential proteins to
promote reverse cholesterol transport, and therefore
down-regulated cholesterol efflux in mice and human
macrophages [260].
During the last years a new hypothesis
regarding the pathogenesis of atherosclerosis as gained
support: that a dietary factor might be the underlying
original cause, potentiated by the already known risk
factors [261]. It has been suggested that this factor is
trimethylamine N-oxide (TMAO). TMAO is derived
from trimethylamine (TMA), which is found in many
animal-derived diet products, such as meat, milk and
fish. TMA is released from these aliments by gut
microbiota metabolism which, therefore, would play an
essential role in the development of the disease [262].
TMA is afterwards absorbed, transported to the liver
and oxidized by flavin-containing mono-oxygenase 3
(FMO3) to the damaging TMAO. Thus, an everyday
increasing number of studies correlate TMAO with the
pathogenesis of metabolic and cardiovascular diseases,
such as atherosclerosis [263]. To our knowledge, so far
only the effects of a flavonoid, phloretin, has recently
been tested in a mouse model of atherosclerosis based
in the TMAO hypothesis. Thus, a group of mice feed a
high-choline diet for 10 weeks also received the
dihydrochalcone phloretin at 100, 200, and 400
mg/Kg/day. The diet caused hyperglycemia,
hyperlipidemia, increased oxidative stress, liver
damage and endothelial dysfunction to control mice.
Phloretin treatment protected from these deleterious
effects, preventing the increase in body weight,
decreasing altered lipid profile, protecting the liver and
the endothelial function [264].
Most of the clinical studies regarding the anti-
atherosclerotic properties of flavonoids have been
made using plant extracts, tea or polyphenol or
flavonoid-enriched aliments [254, 265-267], therefore,
making impossible to know the exact properties and
effects of every isolated flavonoid. For these reasons,
in this review we have preferably taken into account
clinical studies involving single flavonoids, although
some using mixtures or enriched aliments will be
mentioned for their clarifying results. Thus, it has been
reported that 450 mg/day hesperidin 2S (an enantiomer
similar to natural hesperidin but specifically developed
to have improved bioavailability) intake for 6 weeks
improved endothelial function after a high fat meal and
reduced adhesion molecules in overweight and obese
healthy volunteers with a flow mediated dilation
greater or equal to 3%. The treatment only showed a
tendency in the general studied population.
Nonetheless, the flavonoid proved to confer
cardiovascular benefits to overweight and obese people
with a healthy functional endothelium [268]. In another
randomized, double-blind, placebo controlled trial,
both (-)-epicatechin (100 mg/d) and quercetin-3-
glucoside (160 mg/d) intake for 4 weeks in 37 pre or
hypertensive men and women were analyzed.
Treatment with (-)-epicatechin decreased adhesion
molecule E-selectin, while quercetin treatment was
able to reduce E-selectin and interleukin-1 beta (IL-1β)
serum levels, together with a lower z score for
biomarkers of inflammation. Due to the essential role
of inflammation in the pathogenesis of atherosclerosis,
and the fact that E-selectin concentrations in patients
with carotid artery atherosclerosis have been described
to be 15% higher than in controls, these results show
that these flavonoids can contribute to the beneficial
effects of cocoa and tea by improving endothelial
function and decreasing inflammation [182]. Quercetin
also proved to have antiatherogenic effects in a double-
blind crossover study with 49 healthy male subjects
with APOE genotype [269]. Thus, 150 mg/d intake of
quercetin for 8 weeks reduced waist circumference and
postprandial systolic BP in all subjects combined.

12 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
Postprandial triacylglycerol levels were decreased and
HDL-cholesterol increased just after comparison to
placebo. However, endothelial function was unaffected
and TNF-α levels were paradoxically slightly increased
with the treatment. Genotype-dependent effects were
only seen on waist circumference and body mass index
(BMI). Therefore, quercetin had some beneficial
effects on BP and lipid profile, although also exerted
slightly proinflammatory actions. Regarding studies
with enriched aliments and complex mixtures of
flavonoids, in a double-blind randomized controlled
trial, 93 postmenopausal women with type 2 diabetes
mellitus were administered 27 g flavonoid-enriched
chocolate/day (90 mg epicatechin + 100 mg
isoflavones (aglycone equivalents)/day) or placebo to
study if this combination of isoflavone and flavan-3-ol
intake affected vascular function. Treatment did not
affect intima-media thickness in the carotid artery,
although improved pulse pressure variability. In
patients with pulse wave velocity data, higher
improvement was observed, equivalent to a 10%
cardiovascular risk reduction. In equol producer
women, that is, women who produced the isoflavone
daidzein metabolite equol (17 women, 18% of the
study population), larger reductions in diastolic BP,
mean arterial pressure, and pulse wave velocity were
observed. Therefore, the study showed improvements
in arterial stiffness of clinical importance [267],
probably also of relevance to atherosclerotic patients
also suffering from arterial stiffness. Finally, in a
randomized, double-blind trial, 150 subjects with
hypercholesterolemia, a known risk factor for
atherosclerosis, were administered a purified
anthocyanin mixture, 640 mg/day for 24 weeks.
Anthocyanins decreased C-reactive protein and
VCAM-1 serum level, together with plasma IL-1β.
Moreover, there were significant increases in HDL-
cholesterol and decreases in LDL-cholesterol levels
after the treatment. In later in vitro studies, isolated
anthocyanins showed to have additive or even
synergistic anti-inflammatory effects [270]. The
observed improvements in the inflammatory status and
the lipid profile could contribute to a decreased
atherosclerotic risk in hypercolesterolemic patients by
anthocyanins.
FLAVONOIDS, OBESITY, INSULIN
RESISTANCE AND TYPE 2 DIABETES
Obesity, insulin resistance and type 2 diabetes
are intimately linked together, as obesity and insulin
resistance are independent risk factors (among others,
such as hypertension, nonalcoholic fatty liver (NAFL)
and polycystic ovary syndrome) for the development of
type 2 diabetes [271, 272]. These pathophysiological
states share common molecular mechanisms and
metabolic pathways [273-278] and, moreover, play an
important role in the progression of CVD [277, 279,
280], which are the leading cause of death among
diabetic patients [281, 282]. Due to the many actions of
flavonoids, their ubiquity in the vegetable kingdom
and, therefore, in our daily diet, it is reasonable to think
that flavonoids are able to interact whit some of these
molecular processes and prevent or reduce obesity,
insulin resistance and, ultimately, type 2 diabetes.
Flavonoids and Obesity
According to the World Health Organization
(WHO) and based on BMI determination, overweight
or pre-obese people are defined as having a BMI from
25.0 to 29.9 Kg/m2, while obese people are defined as
having a BMI higher than, or equal to, 30.0 Kg/m2.
Despite the fact that in the development of obesity are
also involved environmental and genetic factors,
unhealthy lifestyles such as hypercaloric diets (which
are rich in fats and/or refined carbohydrates but low in
polyunsaturated fatty acids, vegetables and fiber)
together with sedentariness or lack of physical exercise
are the leading cause of obesity. In western countries
overweight and obesity became an epidemic disorder
around 30 years ago [283-285]. Recently, however,
they have spread out to Asian countries as well [284,
286], being a global pandemic nowadays.
Prevention and treatment of overweight and
obesity can be achieved by keeping or restoring the
balance between the energy that enters the body
through foods and drinks in the form of lipids, proteins
and carbohydrates, and the energy that is utilized for
daily activities and the metabolism to maintain body
functions. Flavonoids can act at both levels, through
different mechanisms, to keep or restore a healthy
balance between energy intake and energy expenditure
[287]. It has been described that procyanidins with high
degree of polymerization can inhibit pancreatic lipase
[288], the enzyme that breaks down triglycerides so
they can be absorbed in the gut. Interestingly, the same
is true for (-)-epicatechin gallate, (-)-epigallocatechin
and EGCG [289] which, when polymerized, form
procyanidins. But, moreover, this inhibitory action has
also been described for other flavonoids such as rutin,
hesperidin, kaempferol-3-o-rutinoside [290],
theaflavin, theaflavin-3-O-gallate, theaflavin-3’-o-
gallate, theaflavin-3, 3’-o-gallate, (-)-epicatechin, (+)-
catechin and quercetin-3-O-glucoside [291]. Therefore,
by reducing the quantity of lipids digested, these

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 13
compounds could decrease the amount of triglycerides
absorbed and hence, the fat stored, preventing or
reducing obesity due to a high-fat diet.
Flavonoids are also able to inhibit the main
enzymes responsible for the digestion of carbohydrates,
α-glucosidase and amylases [74]. For instance, in a
study using yeast and rat's small intestine α-glucosidase
together with porcine pancreatic α-amylase to test in
vitro α-glucosidase and α-amylase inhibitory activities
of 16 compounds (luteolin, apigenin, quercetin,
kaempferol, fisetin, genistein, daidzein, (-)-epicatechin,
(-)-epigallocatechin, EGCG, myricetin, (+)-catechin,
baicalein, naringenin, hesperetin, and cyaniding),
representing in total six different groups of flavonoids,
all of them were able to inhibit the enzymes (except for
daidzein with the rat α-glucosidase), being rat α-
glucosidase more resistant to flavonoids action [292].
In addition, in another experiment, the authors found
that luteolin, myricetin and quercetin were the most
potent inhibitors of porcine pancreatic α-amylase,
being all the other flavonoids, although weak, also
inhibitors of the enzyme. Other studies have shown the
same inhibitory properties in digestive enzymes by
several flavonoids from different sources [293, 294].
Since inhibitors of these enzymes can retard the
absorption of carbohydrates and reduce postprandial
hyperglycemia, compounds with these actions, such as
many flavonoids, have recently attracted great attention
because they could be used as new and promising tools
for the prevention and treatment of obesity and type 2
diabetes.
Another mechanism to reduce the uptake of
carbohydrates, and therefore the calories stored as fat,
is by reducing the activity or the number of glucose
transporters. It has been demonstrated that some
flavonoids, such as quercetin, myricetin, fisetin and
isoquercitrin are able to inhibit glucose transporter 2
(GLUT2), one of the main glucose transporters from
the gut lumen to the capillaries on the basolateral side
of the enterocyte, and thus, to reduce the amount of
glucose reaching the blood stream [12]. There are other
important glucose transporters, such as GLUT1, mainly
expressed in erythrocytes, or GLUT4, whose activity is
insulin-dependent. Inhibition of these glucose
transporters or of their translocation, therefore reducing
glucose uptake, has also been demonstrated for several
different flavonoids and in different cells, such as in
cancer cells by phloretin, quercetin or hesperetin [295-
297] and adipocytes by baicalein [298], showing that
this is probably a common mechanism of many
flavonoids. Interestingly, it has also been observed the
opposite effect, that flavonoids augment glucose uptake
by muscle cells, such as diosmin in streptozotocin
(STZ)-induced diabetic rats reducing by this
mechanism glucose blood levels as well [299]; rutin
and quercetin under oxidative stress conditions in
myoblasts [300]; (-)-epicatechin-3-O-β-D-
allopyranoside in STZ-induced diabetic mice, reducing
the levels of blood glucose, and increasing the levels of
insulin [301]; and the flavone tricin in mice myoblasts
[302]. This observed reduction in intestinal glucose
absorbance but increased muscle uptake, could prevent
hyperglycemia by reducing the level glucose absorbed
or in the blood. In fact, a recent systematic review and
meta-analysis stated that, although low carbohydrate
diets are convenient to control weight, reduce the
amount of saturated fatty acids and increase the intake
of active compounds (such as flavonoids, vitamins and
unsaturated fatty acids) seems to be the best strategy to
prevent metabolic syndrome (the combination of at
least three of the following conditions: central obesity,
elevated BP, elevated plasma glucose and
dyslipidemia) [303]. Therefore, there are many
evidences that indicate that the intake of flavonoids
would be of benefit to prevent weight gain due to the
accumulation of extra calories, but also, to people
suffering from insulin resistance and diseases such as
metabolic syndrome and diabetes.
As it was previously said, to keep a healthy
energetic balance a mechanism could be to reduce food
absorption, but another mechanism could consist of
also increase the expenditure of energy so the balance
remains stable. In this regard, flavonoids have been
proposed to increase energy expenditure through
different mechanisms. Green tea catechins inhibit
catechol-O-methyltransferase (COMT), one of the
main enzymes involved in the metabolization of
epinephrine and norepinephrine. Catechins, when
ingested with caffeine, as in green tea, can produce a
synergistic effect, allowing the activity of the
sympathetic nervous system to act longer and,
therefore, consume more energy [304]. When taking
270 mg EGCG plus 150 mg caffeine, energy
expenditure increased 4% in 24 hours compared to
controls [305]. Despite later studies failing to see an
increase on energy expenditure in similar conditions
[304], a meta-analysis concluded that there was a
statistically significant association between green tea
catechins plus caffeine consumption and body weight
reduction [306], probably due to fatty acid oxidation
and increased energy expenditure among other
mechanisms. A very recent study confirmed these
findings performing two controlled randomized trials:
acutely administered, a beverage containing 615 mg tea

14 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
catechin and 77 mg caffeine, compared to a control
beverage which contained 0 mg catechin and 81 mg
caffeine was able to increase energy expenditure,
which was associated with increased brown adipose
tissue (BAT) activity. When chronically administered,
the same beverage was able to elevate non shivering
cold-induced thermogenesis [307]. In contrast to white
adipose tissue (WAT), which just stores extra energy as
fat, BAT increases energy expenditure by generating
heat through nonshivering thermogenesis, as shown in
the previously mentioned study. Related to this effect,
researchers have just found that the flavonol quercetin
is able to remodel white adipocytes to brown-like
adipocytes [308]. This browning-effect seemed, at least
in part, mediated by AMP-activated protein kinase
(AMPK) activation. Therefore, through this conversion
of the type of fat, quercetin could increase energy
expenditure, decreasing the accumulated calories and
helping to lose weight or preventing to gain it. Studies
conducted with other flavonoids, such as chrisin [309]
and luteolin [310] have shown the same adipocyte
browning properties, hence, it could be a general
mechanism shared by more flavonoids. Similar effects
on increasing energy expenditure have also been
demonstrated in animal studies testing a different
flavonoids. In leptin receptor-deficient db/db mice,
myricetin (400mg/Kg/day for 14 weeks) was able to
increase energy expenditure, measured by indirect
calorimetry (and without difference in physical activity
between groups) and by increased BAT activity through
PET-CT imaging. It was also accompanied by a body
weight reduction and an improvement on insulin
resistance and other obesity related parameters when
compared to control mice [311].
A different mechanism by which flavonoids
can prevent and reduce obesity is due to their inhibitory
actions on adipogenesis and fat accumulation. It has
been shown that during the differentiation of
preadipocytes (3T3-L1 cells) to adipocytes, incubation
with quercetin (100µM) inhibits by more than 15%
intracellular lipid accumulation [312]. In the same
study, researchers found that, in mature adipocytes, the
same dose of quercetin decreased viability by more
than 15% while increasing apoptosis by 85% at 48
hours. In line with these findings, recently it has been
shown that in the above mentioned preadipocytic 3T3-
L1 cells, when turned into hypertrophic adipocytes
both, quercetin and its main metabolite in blood
circulation, Q3GA, are absorbed by these cells,
metabolized to some extent to Q3GA and quercetin
respectively and then, they are able to diminish
intracellular ROS levels in those cells [313]. Another
study has just found that quercetin 3-O-glucoside
reduced in a dose-dependent way triglyceride content
and lipid accumulation in the mentioned preadipocytic
3T3-L1 cells almost twice more effectively than
quercetin, and that these effects were also related to an
enhanced inhibition of adipocyte differentiation and
lipogenesis in vitro. In vivo, quercetin 3-O-glucoside
also showed a stronger anti-obesity effect than the
aglycone alone, in mice feed a HFD, when
administered for 6 weeks at a dose of 30 mg/Kg body
weight. It was shown that the anti-obesity effects were
mediated via inhibition of adipocyte differentiation and
lipogenesis, resulting in lower serum lipid levels by
altering hepatic lipid metabolism and thus, reducing
body weight gain [314]. Therefore, not just the
aglycones, but also their metabolites may account for
the observed effects of flavonoids on adipose tissue,
and what is more, these metabolites could be even
more effective that the aglycones themselves, which
increases the difficulty of the research in this field.
Several other flavonoids have also been shown to
decrease lipid accumulation in these preadipocytic
cells, being rutin the most potent inhibitor among them
[315]. However, flavonoids did not affect the level of
apoptosis of those cells. In addition, when studied in
vivo, a dose of 50 mg/Kg/day of rutin for 8 weeks
decreased adipose tissue and body weight gain in rats
on a 12 week HFD [316]. Similar results were observed
in zebra fish feed a HFD for 15 days, where
kaempferol decreased in a dose-dependent way lipid
accumulation, visualized by Nile red staining, and
expression of adipogenic factors [317], supporting
therefore, the observed anti-adipogenic and anti-obesity
properties of flavonoids.
Adipose tissue also possesses endocrine
functions and is able to modulate the immune response,
releasing pro- or anti-inflammatory adipokines,
depending on the circumstances. Thus, a chronic low
level inflammatory status has been associated with
obesity [287, 318]. Flavonoids, such as quercetin,
luteolin and EGCG have anti-inflammatory properties
in adipose tissue, inhibiting NF-κB, TNF-α, MCP1 and
IL-6 in preadipocytes while, on the other hand, activate
AMPK, SIRT1 and increase the levels of adiponectin
[319]. The flavone tilianin, administered for 10 days at
a dose of 60mg/kg/day to STZ-Nicotinamide diabetic
rats, reduced gene expression of ICAM-1 in aorta, IL-
1β and IL-18 in adipose tissue, without modifying
TNF-α or MCP-1 expressions and increased the
expression of adiponectin [320]. These anti-
inflammatory properties of flavonoids in adipose tissue
could help normalize adipose tissue low-grade

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 15
inflammation observed in obesity and, therefore, be
one of their molecular mechanisms to prevent fat
accumulation and reduce adipogenesis, due to the close
link, and apparently regulatory feedback mechanism,
between the immune system and obesity.
The best proof for the utility of flavonoids to
prevent and treat overweight and obesity would be
trials showing a direct weight loss due to their intake.
However, despite a general tendency to believe in the
beneficial effects of these compounds, and some
favorable studies as the previously stated, some reports
show contradictory results about their effects on body
weight, both in animals and in humans. For instance,
Duarte et al. did not see any change in body weight in
four different models of hypertensive rats, nor in their
normotensive counterparts, when administered with the
flavonol quercetin at a dose of 10 mg/Kg of body
weight/day for 4, 5, 6 or event 13 weeks [46, 47, 54,
55, 183, 189]. There was, however, a clear tendency,
although not statistically significant, to a reduced body
weight in the DOCA-salt hypertensive rat model. They
did not find a difference in body weight either when
administered the flavone chrysin (20 mg/Kg of body
weight) for 6 weeks to SHR and their normotensive
controls [321]. Interestingly, (-)-epicatechin, at a daily
dose of 10 mg/Kg of body weight for 5 weeks, but not
at a dose of 2 mg/Kg of body weight, was able to
reduce body weight in the DOCA-salt model, being
without effect in the normotensive control group.
Yamamoto and Oue found a reduction in the body
weight gain of a group of rats with a high-fat high-
sucrose diet taking a dose of 0.5% quercetin for four
weeks [194]. Other studies have shown the same
apparently contradictory results using quercetin,
cyanidin 3-glucoside or epigallocatechin gallate, but
three studies in mice and rats using rutin showed a
clear reduction in body weight [322]. The reduction in
body weight seen in the disease animal models, but not
in the control animals, seems to be due to the balance-
restoring effects of flavonoids, being effective only
under oxidative stress circumstances, when the pro-
oxidant/antioxidant balance is disrupted, such as occurs
in hypertension and obesity. In humans, despite studies
using complex flavonoid mixtures such as green tea,
proving their effects on body weight loss [304-306,
323, 324], there are no conclusive results yet, as other
studies with flavonoid mixtures and even specific
flavonoids have not seen similar results on body weight
reduction [209, 268, 325-328]. Therefore, there is still
the need for more studies involving individual
flavonoids, not just plant extracts or polyphenol
mixtures as the majority of the studies so far have used.
These mixtures and extracts rich in flavonoids have
demonstrated interesting effects regarding prevention
of overweight or obesity and on body weight reduction,
but they are difficult to attribute to a determined
flavonoid. Therefore, larger, longer in time and better
designed, ideally randomized, double-blind control
trials, using single and standardized flavonoids, are
needed to completely clarify the effects of flavonoids
on body weight.
Flavonoids in Insulin resistance and Type 2 diabetes:
Obesity, an unhealthy diet and the lack of
physical exercise, together with genetic predisposing
factors, can cause the inability of the cells to use
insulin efficiently to store glucose. This state is called
insulin resistance, because more insulin than in a
normal, healthier situation is needed. In these
circumstances the pancreatic β-cell mass increase to
compensate for insulin resistance and the blood levels
of insulin will increase, therefore leading to
hyperinsulinemia. If this situation is maintained, the
body is not able to store glucose properly, a pancreatic
β-cell dysfunction appears and the level of glucose in
blood finally rises. Thus, these increased levels of the
carbohydrate will cause hyperglycemia, a prediabetic
state [329, 330]. Both, hyperglycemia and
hyperinsulinemia are complex metabolic disorders that
will progress until the development and onset of type 2
diabetes, with all its complications, if not treated in
time [331-333].
As it has been mentioned above, flavonoids,
due to their capabilities to prevent and reduce
overweight and obesity, could be helpful to also
prevent and treat insulin resistance and type 2 diabetes.
It is due to their ability to inhibit glucose transporters
[12, 295-298] and carbohydrate-digestive enzymes
such α-glucosidase and amylases [292-294] and
increase glucose uptake by different cells [299, 300,
302]. Thus, preventing the rise of postprandial glucose,
these compounds could become important tools to
manage prediabetic states or even reduce blood glucose
levels in already established type 2 diabetes.
AMPK is a key enzyme regulating the
translocation to the cell membrane of glucose
transporters GLUT1 and GLUT4 and, therefore, of the
glucose uptake in skeletal muscle and other tissues
[334]. Moreover, its activation seems to favor insulin
secretion and protect pancreatic β-cells from
glucolipotoxicity [335]. Substances able to activate
AMPK and therefore increase glucose transport from
the blood to the tissues can decrease the level of blood
glucose. In fact, some glucose lowering drugs are

16 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
AMPK activators, such as metformin and
thiazolidinediones [334]. Thus, it has been shown that
some flavonoids, such as quercetin [336], apigetrin
[337], baicalein [338], kaempferol [339] and
naringenin [340] are able to increase AMPK activity in
skeletal muscle, lung, macrophages, adipose tissue and
endothelial cells. Consequently, these compounds can,
through the activation of this key metabolic regulatory
enzyme, improve insulin resistance, reduce
hyperglycemia and have a positive impact in pre and
diabetic patients, as seen in vitro and in the animal
models of the disease.
As it was explained earlier, thiazolidinediones,
also known as glitazones, are a family of drugs
commonly used to treat diabetes. Although they also
activate AMPK among other actions, its main
mechanism of action is, however, due to the activation
of PPARγ, a group of nuclear receptors which act as
transcription factors for several genes, regulating fatty
acid accumulation, glucose and lipid metabolism and
therefore, energy balance. Some flavonoids have been
shown to also be able to activate PPARγ. Thus, chrysin
increased mRNA expression of PPARγ in macrophages
and also the expression of PPARγ-dependent genes
[341]. EGCG was also able to increase PPARγ mRNA
and protein expression in the N2a/APP695 cell line
[342]. Another flavonoid, puerarin, protected against
transverse aorta constriction-induced cardiac fibrosis in
mice, and the protective effects were attributed, at least
in part, to the upregulation of PPARγ [343]. Even more
interesting, luteolin reduced obesity and insulin
resistance in mice feed a HFD supplemented with
0.002 or 0.01% luteolin for 12 week. These effects
were attributed to an improvement on the inflammatory
status and a regulatory effect on PPARγ [344]. Similar
results were obtained by these authors in the same
model, when administering the HFD supplemented
with luteolin 0.01% for 20 weeks. This time, they also
reversed pre-established insulin resistance, decreased
macrophage infiltration to adipose tissue, inhibited
classic and metabolic-activated macrophage
polarization and, interestingly, these anti-inflammatory
results were attributed to an AMPKα1 activation in
these adipose tissue macrophages [345]. Also recently,
it has been shown that the flavonoid ampelopsin (or
dihydromyricetin) is able to improve insulin resistance
in palmitate-induced insulin resistance of L6 myotubes,
through the activation of PPARγ [346]. Conversely, the
anti-obesity and anti-diabetic effects on high fat feed
mice of a fraction containing four kaempferol
glycosides, was related to a downregulation of PPAR-γ
[347]. Therefore, more research is needed to
completely understand the effects of flavonoids on
PPARγ activity, since some of them have shown
opposite actions [347, 348], and their relationships with
their anti-obesity and anti-diabetic properties.
Many flavonoids are actually able to prevent or
reduce diabetes, as many studies using experimental
models have proven. For instance, the (-)-epicatechin
glycoside (-)-epicatechin-3-O-β-D-allopyranoside, was
able to prevent diabetes and dyslipidemia in STZ-
induced diabetic mice when administered by oral
gavage once daily at either of three different doses: 10,
20, or 40 mg/Kg for a period of 28 days [301]. Also
using the diabetes model of the STZ-induced diabetic
rats and a model of insulin resistance of rats feed with a
high fructose (10%) diet for 12 weeks, the treatment
with quercetin (50 mg/Kg/day by oral gavage) for 6
weeks reduced increased vasoconstriction due to
diabetes and BP, as well as some inflammatory
markers. However, quercetin did not modify glucose
levels in any of these disease models. Nonetheless, this
study showed that quercetin could be used to prevent
diabetic cardiovascular complications in insulin
resistance and diabetes [97]. The important antioxidant
activity of flavonoids in their anti-diabetic effects was
clearly shown in a study where hesperidin and
naringin, at a dose of 50mg/Kg/day for 30 days or 4
weeks respectively, both reduced glucose blood levels,
glycated hemoglobin (HbA1c), and inflammatory and
oxidative stress markers while potentiating the body’s
antioxidant system by increasing liver antioxidant
enzymes, liver and serum glutathione, and serum levels
of vitamins C and E in high fat feed/STZ-induced
diabetic rats [349]. Naringin also reduced serum insulin
and glucose levels, insulin resistance, improved
dyslipidemia, β-cell dysfunction and kidney damage in
high fat feed/STZ-induced diabetic rats [350]. These
effects were related to PPARγ increased expression in
liver and kidney. In a mouse model of metabolic
syndrome induced by a HFD, baicalein (400
mg/Kg/day) improved insulin resistance and
hyperlipemia, reduced glucose blood levels, abdominal
obesity and serum inflammatory markers [351].
Intriguingly, these effects were attributed to AMPK
activation, but PPARγ downregulation. Silibinin (or
silybin), one of the components of silymarin, a natural
flavonoid complex obtained from milk thistle and
formed by 4 flavanolignans: silicristin, silidianin,
silybin and isosilybin, decreased fasting glucose and
insulin, reversing insulin resistance and also improving
endothelial dysfunction, without altering body weight,
in db/db obese mice when daily administered a dose of
20 mg/Kg intraperitoneal for 4 weeks [352]. Another

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 17
group of researchers also showed the effects of silibinin
(100 mg/Kg/day, by gastric intubation, for 8 weeks),
preventing the progression of insulin resistance and
restoring antioxidant system in the gerbil Psammomys
obesus model of diabetes [353]. Also using the STZ-
induced diabetic rat model of diabetes, recently, the
glycosylated flavonoid vitexin, administered at a dose
of 1 mg/Kg by oral gavage for 8 weeks, was able to
significantly reduce fasting blood glucose, increase
whole-body blood glucose disposal, decrease insulin
resistance and blood triglycerides and reduce
pancreatic oxidative stress while facilitating pancreatic
β-cells regeneration, increasing pancreatic glutathione
peroxidase and serum n-3 polyunsaturated fatty acids
[354]. Apigenin and naringenin, in a similar STZ-
induced diabetic rat model but also using HFD to
mimic diabetes, were tested at two different doses (50
and 100 mg/Kg/day) during 6 weeks. They decreased
fasting blood glucose and serum glucose levels,
normalized serum lipid profile, reduced oxidative stress
markers, improved insulin resistance and increased
SOD activity and glucose tolerance at all doses.
Apigenin seemed to have more powerful anti-diabetic
properties than naringenin. These effects were
moreover accompanied by an improvement of the
aortic endothelial dysfunction in the treated rats
compared to controls [355]. In a completely different
model suffering from insulin resistance, a polycystic
ovary syndrome rat model, quercetin has recently been
able to reduce insulin resistance when administered at a
dose of 100mgl/Kg/day by oral gavage during 28 days.
The flavonoid reduced fasting blood glucose and
insulin levels, together with inflammatory markers in
rat ovaries [356]. Finally, in a mouse model of HFD-
induced insulin resistance, (-)-epicatechin, ingested
mixed with the HFD at a dose of 20mg/Kg for 15
weeks, improved insulin sensitivity, fasting and feed
blood glucose levels and also reduced increased insulin
level caused by HFD. These results were attributed to
an increased phosphorylation and activity of proteins
involved in the insulin signaling cascade in adipose
tissue and liver, such as insulin receptor (IR), insulin
receptor substrate 1 (IRS1), Akt, or ERK1/2 [357].
Apart from the mentioned results using animal
models, there are several clinical studies testing the
efficacy of flavonoids improving insulin resistance
and/or diabetes in humans. However, most of them
made use of plant extracts rich in flavonoids,
sometimes analyzed for content and composition after
the study of their properties. We are only going to take
into account studies of individualized flavonoids, not
extracts, despite the fact that some of them have also
shown anti-diabetic properties, but difficult to attribute
to a single substance. In a recent meta-analysis 18
studies using a single flavonol or a fixed combination
of two of them, were analyzed [358]. The flavonols
used were mainly quercetin, but also dihydromyricetin,
rutin, quercetin-3-glucoside and isorhamnetin. The
meta-analysis concluded that the intake of flavonols
was beneficial from the point of view of blood glucose
and lipids, BP and therefore contributed to a lower risk
of CVD. For example, a significant reduction in fasting
glucose levels after flavonol supplementation was
observed. However, it was also made clear that
individual characteristics influenced their effects,
mainly ethnicity, disease, and baseline levels, and
therefore these factors, together with gender, age, BMI,
lifestyle factors, diet and physical activity should be
reported in future studies to obtain clear results and
appropriate to be translated into clinical practice and to
diet and lifestyle recommendations to the population.
Another small meta-analysis, this one studying the
effects of silymarin [359], found that its administration
was associated with a significant reduction in fasting
blood glucose and HbA1c levels, an indicator of blood
glucose levels in the last 3 months. However, due to the
scarce evidence (5 studies analyzed), more studies are
needed. In some diseases there can also be a metabolic
disorder involving insulin resistance, increased blood
glucose and low adiponectin levels, similar to what
occurs in diabetes. This is the case of polycystic ovary
syndrome. In fact, polycystic ovary syndrome is
regarded as a kind of metabolic syndrome due to
symptoms such as dyslipidemia, obesity, high BP, and
increased inflammation. Moreover, almost 50% of
polycystic ovary syndrome patients suffer from obesity
and insulin resistance. Thus, researchers found that
quercetin intake (1000mg/day) for 12 weeks was able
to improve insulin resistance and reduce fasting blood
glucose in women diagnosed with polycystic ovary
syndrome [360]. Likewise, in a double-blind clinical
trial on NAFL disease patients, whom also had insulin
resistance, increased blood glucose and high levels of
inflammatory markers, treatment with
dihydromyricetin (600 mg/day) for three months
improved insulin resistance while decreasing high
glucose and inflammatory markers without changing
insulin levels [361].
In spite of these promising results with some
flavonoids, in a randomized, double-blinded trial in
healthy men with high baseline plasma uric acid
concentration, but below an unhealthy level or those to
develop gout, with the consumption of 500 mg of

18 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
quercetin daily for 4 weeks, researchers did not find a
reduction in fasting glucose, despite they found a
significant reduction in plasma uric concentration
[362]. This could be due to the fact that these studied
patients had normal to slightly impaired fasting blood
glucose levels, maybe even without insulin resistance,
which was not evaluated. Accordingly, flavonoids were
likely not able to improve this already healthy glucidic
metabolism. In view of the great number of positive
and promising results, but also the number of unsolved
questions (such as the most useful flavonoid to prevent
or treat diabetes in humans, the ideal dose or daily
intake, the main mechanism of action, the possible
interaction with other natural compounds or drugs, etc.)
as occurs with the role of flavonoids regarding body
weight, more research is needed, with single or
standardized mixtures of flavonoids, using randomized,
double-blind control trials in a wide range of patients,
to unravel the complex mechanisms and effects of
flavonoids on insulin resistance, carbohydrate
metabolism and diabetes.
FLAVONOIDS AND MYOCARDIAL ISCHAEMIA
Chronic coronary disease and the acute
coronary syndromes are responsible for a number of
deaths, especially in Western society. They involve
multiple alterations in vascular reactivity, vascular
structure, and interactions of the vessel wall with
circulating blood elements. The main risk factors for
myocardial infarction are hypertension and
atherosclerosis. In fact, reduction of LDL-cholesterol
and atherosclerotic lesions and BP produces a dramatic
decline in the risk of coronary disease [363].
Furthermore, endothelial dysfunction is an independent
prognostic factor for myocardial infarction [364, 365].
As reviewed above, flavonoids may protect the
coronary vessels in the long term by preventing
hypertension, atherosclerosis and endothelial
dysfunction.
In acute myocardial ischemia cell death and
loss of cardiomyocyte population are a consequence of
the reduced coronary blood supply. Most acute
coronary events result from a rupture in the
atherosclerotic plaque, thrombus formation and the
subsequent myocardial ischemia. Degradation of the
interstitial collagen conferring biomechanical strength
to the plaque fibrous cap by MMPs appears to be
involved in the plaque instability and its rupture.
Quercetin reduces the expression of MMP-2 and
MMP-9 [366] and may help in stabilizing the
atherosclerothic plaque [367]. Other flavonoids such as
EGCG, (-) epicatechin, baicalein and kaempferol down-
regulate MMPs interfering with VEGF signaling,
inhibition of NF-κB and mTOR expression, and other
mechanisms [368]. Coronary vasospasm may also
contribute to acute impaired arterial flow. Flavonoids
by their platelet antiaggregant and vasodilator effects,
as reviewed above, may also provide additional
protective benefit in the acute phase. To reduce
ischemic damage the most effective strategy is an early
reperfusion. Paradoxically, during the ischemic event
and the eventual post-ischemic reperfusion there is an
acute inflammatory process with the release of multiple
cytokines and ROS. Post-ischemic reperfusion
occurring in coronary diseases is generally associated
with a reduction of endogenous NO production
resulting from endothelial dysfunction and tissue
damage linked to neutrophil infiltration. In addition,
ROS regulate mitochondrial functions inducing the
irreversible opening of the mitochondrial permeability
transition pore (mPTP) leading to myocardial cell
death. Recently, Testai et al. (2015) reviewed the
experimental studies performed to examine the
cardioprotective activity of flavonoids on several
experimental models of myocardial
ischemia/reperfusion (I/R) injury. These agents
improved cardiac functional recovery, increased
coronary flow, reduced oxidative damage and protected
from cell death. The antioxidant, anti-inflammatory,
vasodilator and mitochondriotropic activities are
involved in the cardioprotection against I/R injury. The
main flavonoids that have been described to induce
cardioprotective effects in animal models of ischemia
are quercetin, luteolin, EGCG, (-)-epicatechin,
naringenin and antocyanin [369].
In the seminal epidemiological report (Hertog
et al., 1993), flavonoid intake (analysed in tertiles) was
strongly inversely associated with mortality from
coronary heart disease [relative risk 0.42 (95% CI 0.20-
0.88)] after adjustment for known risk factors and other
dietary components. An inverse relation with incidence
of myocardial infarction, which was of borderline
significance, was also noted [370]. A number of similar
epidemiological studies followed in the United States
of America and Europe. However, although several
cohort studies support the inverse association between
flavonoid intake and risk of mortality of CVD, many
variability factors emerge, hindering the interpretation
of data, such as food composition an variability in
flavonoid content [371]. In addition, another aspect of
variability is related to the different flavonoid classes,
because they are different in bioavailability and
bioactivity. The first meta-analysis of these prospective
cohort studies concluded that the individuals in the top

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 19
third of dietary flavonol intake are associated with a
reduced risk [0.80 (95% CI 0.69-0.93)] of mortality
from coronary heart disease as compared with those in
the bottom third [71].
Five flavonoid classes-anthocyanidins, flavan-
3-ols, flavones, flavonols, and proanthocyanidins-were
individually associated with lower risk of fatal CVD
(all P-trend < 0.05). Peterson et al., (2012) review the
twenty publications from twelve prospective cohorts
that have evaluated associations between flavonoid
intakes and incidence or mortality from CVD among
adults in Europe and the United States. They found that
the flavonol and flavone classes were most strongly
associated with lower coronary heart disease mortality.
Evidence for protection from other flavonoid classes
and CVD outcomes was more limited. Similarly,
Jacques PF et al., (2015) found that only flavonol
intake was significantly associated with lower risk of
CVD incidence in the Framingham Offspring Cohort.
In contrast, Dower JL et al., (2016), using data from the
Zutphen Elderly Study showed that epicatechin intake
is inversely related to coronary heart disease mortality
in elderly men and to CVD mortality in prevalent cases
of CVD. Moreover, an inverse association between
nonfatal myocardial infarction and anthocyanin intake,
which was stronger in normotensive participants [372],
and between anthocyanidin and proanthocyanidin
intakes and incident coronary heart disease in
participants enrolled in the REGARDS (REasons for
Geographic and Racial Differences in Stroke) study
[373] was described.
FLAVONOIDS AND STROKE
Ischemic stroke is a devastating disease
representing the second leading cause of death in the
Western world and the leading cause of disability in
adults [374]. Acute ischemic stroke results from
transient or permanent reduction in regional cerebral
blood flow, occurring during vascular obstruction by
embolism or local thrombosis [375]. Following
ischemic stroke, neurons are deprived of oxygen and
energy with detrimental effects on energy-dependent
processes in neuronal cells. Immediately after
ischemia, neurons are unable to sustain their normal
transmembrane ionic gradient and homeostasis. This
elicits several processes that lead to cell death:
excitotoxicity, oxidative and nitrative stress,
inflammation, and apoptosis. These pathophysiological
processes are seriously injurious to neurons, glia, and
endothelial cells and are interlinked, triggering each
other in a positive feedback loop that terminates in
neuronal destruction [376]. Compromised, or
completely blocked brain circulation results in a brain
infarct, causing either well defined clinical syndromes,
or occasionally no, or slowly progressing neurological
deficits. The prognosis is dependent on the affected
brain territory of the occluded arterial branches and the
anastomosis system [377].
Several risk factors are involved in the
occurrence of stroke, such as hypertension,
atherosclerosis, LDL-cholesterol, diabetes and atrial
fibrillation. On the base of animal and human
epidemiological studies flavonoids have been proposed
to be effective both as preventive agents and as
treatment options in the acute phase of stroke [378].
Flavonoids present potential mechanisms to prevent
strokes, such as reduction of endothelial dysfunction,
blood cholesterol, atherosclerosis, hypertension and
possibly thrombosis. With regard to acute treatment,
flavonoids may act on different phases of stroke. For
the acute phase, flavonoids improve cerebral blood
flow, prevent platelet aggregation and thrombosis,
reduce excitotoxicity and inhibit oxidative stress. For
the intermediate phase, flavonoids reduce inflammation
and protect endothelial integrity. For the late phase,
flavonoids interfere with ischemia induced cell death
mechanisms such as apoptosis and necrosis [379].
These potential mechanisms have been described
mainly in experimental animal models of stroke, for
flavonoids belonging to several classes.
In vitro and in vivo studies.
Quercetin and kaempferol, in in vitro
conditions, inhibit excitotoxicity. In fact, both agents
significantly reduced neuronal death caused by kainate
plus N-methyl-D-aspartate [380]. The observed
neuroprotection was correlated with prevention of
delayed calcium deregulation and with the maintenance
of mitochondrial transmembrane electric potential.
These flavonols reduced mitochondrial lipid
peroxidation and loss of mitochondrial transmembrane
electric potential caused by oxidative stress induced by
ADP plus iron. Thus, the neuroprotective action
induced by quercetin and kaempferol was mainly
attributed to its antioxidant effects [380]. Moreover,
quercetin abolished hypoxia-induced increase in type 1
and 2 inositol (1,4,5)-trisphosphate (IP3) receptors on
cerebellar granular cells of rat, and regulates
intracellular calcium [381]. Quercetin also effectively
protected cerebellar granule neurons or mesencephalic
dopamine neurons from death induced by oxidative
stress [382, 383]. Recently, human/rat neuroblastoma
cell lines (SHSY5Y and B35, respectively) and E18-
derived rat primary cortical neurons treated with

20 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
quercetin displayed increased tolerance to
oxygen/glucose deprivation exposure, an in vitro model
of ischemia. Quercetin acts to increase survival in the
face of ischemia via an increase of Small Ubiquitin-like
MOdifier (SUMO)-specific isopeptidases (SENP)3
expression, the possible inactivation of SENPs 1/2, and
via a decrease in Keap1 levels (thereby increasing Nrf2
stability). These changes may then lead to increase in
hipoxia-induced factor (HIF)-1α SUMOylation and
HO-1 activation, followed by an up-regulation of
NOS1/ protein kinase G (PKG) signaling [384]. In
vivo, quercetin scavenges superoxide anions released
during reperfusion after forebrain ischemia using a
vessel occlusion model in rats [385], and reduced in
global ischemia-induced neuronal damage, which was
attributed to inhibition of MMP-9 activity [386].
Chronic administration of quercetin has anti-
inflammatory properties in the brain. In fact, in LPS-
treated mice, quercetin inhibits the expression of
proinflammatory enzymes COX2 and iNOS, reversing
LPS-induced memory deficits [387]. In BV-2
microglial cells stimulated by LPS/interferon-gamma,
quercetin produces an inhibitory effect on iNOS and
NO production. The anti-inflammatory action of
quercetin may be attributable to its raft disrupting and
antioxidant effects. These distinct mechanisms work in
synergy to down-regulate iNOS expression and NO
production [388]. Sharma et al. [389] showed that
flavonoids confer protection against IL-1β induced
astrocyte mediated neuronal damage by: (i) enhancing
the potential of activated astrocytes to detoxify free
radical (SOD-1 and thioredoxin-mediators), (ii)
reducing the expression of proinflammatory cytokines
(IL-6) and chemokines (IL-8, IP-10, MCP-1 and
RANTES), and (iii) modulating expression of
mediators associated with enhanced physiological
activity of astrocyte in response to injury. Recently,
combining quercetin treatment with delayed
transplantation of human umbilical cord mesenchymal
stromal cells (HUMSCs) after local cerebral ischemia
in rat significantly (i) improved neurological functional
recovery; (ii) reduced proinflammatory cytokines (IL-
1β and IL-6), and increased anti-inflammatory
cytokines (IL-4, IL-10, and transforming growth factor-
β1); (iii) inhibited cell apoptosis (caspase-3
expression); and (iv) improved the survival rate of
HUMSCs in the injury site [90].
Treatment with isorhamnetin, initiated
immediately at the onset of reperfusion, protected the
brain against ischemic injury in mice, by reducing
apoptosis and inflammation, increasing Nrf2/HO-1
antioxidant defence, and improving blood-brain barrier
(BBB) function [103]. BBB disruption mediated by
proteases plays a pivotal role in neural tissue damage
after acute ischemic stroke. In an animal stroke model,
the activation of MMPs, especially MMP-9, was
significantly increased and it showed potential
association with BBB disruption and cerebral edema.
Treatment with rutin, starting 1h after injury (focal
cerebral ischemia by photothrombosis) and at 12h
intervals for 3 days significantly attenuated MMP-9
expression and activity, reduced BBB permeability and
improved functional outcomes [390]. Icariin, a
prenylated flavonol glycoside extracted from Chinese
medicinal herb Epimedii, has also a neuroprotective
effect on ischemic stroke in rats through inhibition of
inflammatory responses mediated by NF-κB and
PPARα and PPARγ [391].
Several flavonoids were studied for their ability
to induce neurite outgrowth in PC12 cells, which is a
well-studied model system of neuronal differentiation
[392]. It was found that fisetin was the most effective
flavonoid that induced neurite outgrowth by inducing
ERK1/2 activation and PC12 cell differentiation.
Fisetin also inhibited LPS-induced TNF-α production
and neurotoxicity of macrophages and microglia in
vitro by suppressing NFκB activation and c-Jun N-
terminal kinase (JNK)//Jun phosphorylation [393, 394].
In vivo, fisetin not only protected brain tissue against
I/R injury when given before ischemia but also when
applied 3 hours after ischemia. Fisetin also prominently
inhibited the infiltration of macrophages and dendritic
cells into the ischemic hemisphere and suppressed the
intracerebral immune cell activation [394].
Baicalin protected the neuronal cells from
extraneous and endogenous peroxynitrite-induced
neurotoxicity, by directly scavenging peroxynitrite. In
I/R brains, baicalin inhibited the formation of 3-
nitrotyrosine, reduced infarct size and attenuated
apoptotic cell death, whose effects were similar to
FeTMPyP, a peroxynitrite decomposition catalyst
[395]. Similarly to other flavonoids, 7,8-
dihydroxyflavone is able to protect against cerebral I/R
injury, which may be, at least in part, attributable to its
anti-apoptotic, anti-oxidative and anti-inflammatory
actions [26].
Studies have shown that flavanols, such as
epicatechins, catechins, and procyanidins, have great
potential for neurovascular protection. A brain-
permeable flavonoid named (-)-epicatechin modulates
redox/oxidative stress and has been shown to be
beneficial for vascular and cognitive function in
humans and for ischemic and hemorrhagic stroke in
rodents [396]. Recently, epicatechin protects the

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 21
traumatic brain injury (TBI) by activating the Nrf2
pathway, inhibiting HO-1 protein expression, and
reducing iron deposition. The latter two effects could
represent an Nrf2-independent mechanism in this
model of TBI [397]. EGCG, a naturally existing
polyphenol from green tea extracts, has been suggested
to exert beneficial effects against cerebral ischemic
injury [398]. EGCG exhibits antioxidant and
neuroprotective effects after focal cerebral ischemia
[399, 400] and improves forelimb functions after
transient middle cerebral artery occlusion [401].
Particularly, in a recent study, it has also found that
EGCG was able to extend the therapeutic window of
recombinant tissue plasminogen activator (rt-PA)
treatment in ischemic rats [402].
Prophylactic treatment with naringenin
improved functional outcomes and abrogated the
ischemic brain injury induced by middle cerebral artery
occlusion, by suppressing NF-κB-mediated
neuroinflammation [403]. Pinocembrin is a natural
flavonoid compound extracted from honey, propolis,
ginger roots, wild marjoram, and other plants. In
preclinical studies, it has shown anti-inflammatory and
neuroprotective effects as well as the ability to reduce
ROS, protect the BBB, modulate mitochondrial
function, and regulate apoptosis. Therefore, in 2008,
pinocembrin was approved by the State Food and Drug
Administration of China for clinical trials in patients
with ischemic stroke and is currently enrolling patients
for phase II clinical trials [404].
Xanthohumol is the principal prenylated
chalconoid in hops (Humulus lupulus L.), an ingredient
of beer. Treatment with xanthohumol attenuated focal
cerebral ischemia and improved neurobehavioral
deficits in cerebral ischemic rats. This potent
neuroprotective activity is mediated, at least in part, by
inhibition of inflammatory responses (i.e., HIF-1α,
iNOS expression, and free radical formation), apoptosis
(i.e., TNF-α, active caspase-3), and platelet activation,
resulting in a reduction of infarct volume and
improvement in neurobehavior in rats with cerebral
ischemia [405].
Several flavonoids exert in vitro
neuroprotective effect on damage induced by different
stimuli. However, the ability to induce neuroprotection
in some in vivo models might be limited by their
capacity in crossing the BBB and to penetrate into the
brain. For example, quercetin metabolites seem to be
less neuroprotective and penetrate the BBB less
efficiently than the aglycone. However, increased BBB
permeability may occur under inflammatory conditions
as occur in stroke which would facilitate quercetin
brain penetration. When flavonoids were administered
in lecithin preparation to facilitate the crossing of the
BBB, treatment of permanent focal ischemia with this
lecithin/quercetin preparation decreased lesion volume
[406] and increase in numbers of cells in striatum and
cortex, together with a partial reversal of motor deficits
[407].
Epidemiological and intervention studies
Peterson et al (2012) reviewed the twenty
publications from twelve prospective cohorts and they
have evaluated associations between flavonoid intakes
and incidence or mortality from CVD among adults in
Europe and the United States. Three of seven cohorts
reported that greater flavonoid intake was associated
with lower risk of incident of fatal and nonfatal stroke
combined, and these inverse associations were
confined to flavonols (and flavones), and flavanones
(and flavonols and flavones). However, no associations
were observed between flavonoid intakes and fatal
stroke in three different studies of two cohorts [408].
A meta-analsis adressed to determine whether
an association exists between flavonol intake and the
risk for stroke in observational studies, has been
performed by Wang et al., (2014). They conclude that
higher dietary flavonol intake is associated with a
reduced risk for stroke, especially among men,
supporting the recommendations for higher
consumption of flavonol-rich foods to prevent stroke.
Recently, a re-evaluation of a prospective study among
69 622 women from the Nurses' Health Study was
performed [409]. Women in the highest compared with
the lowest quintile of flavanone intake had a relative
risk of ischemic stroke of 0.81 (95% CI, 0.66-0.99;
P=0.04). Citrus fruits/juices, the main dietary source of
flavanones, tended to be associated with a reduced risk
for ischemic stroke (relative risk, 0.90; 95% CI, 0.77-
1.05) comparing extreme quintiles. Total flavonoid
intake was not inversely associated with risk of stroke;
however, increased intake of the flavanone subclass
was associated with a reduction in the risk of ischemic
stroke. Further prospective studies are needed to
confirm these associations. The same group examined
the relation between habitual anthocyanin and
flavanone intake and coronary artery disease and stroke
in the Health Professionals Follow-Up Study.
Anthocyanin intake was not associated with stroke risk.
Although flavanone intake was not associated with
total stroke risk, higher intake was associated with a
lower risk of ischemic stroke (HR: 0.78; 95% CI: 0.62,
0.97; P = 0.03, P-trend = 0.059), with the greatest
magnitude in participants aged ≥65. Lai et al., (2015)

22 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
explore the association between total fruit and fruit
subgroup intake according to polyphenol content and
CVD mortality in the UK Women's Cohort Study. They
found that women in the highest intake group of grapes
and citrus experienced a significant reduction in risk of
stroke compared with non-consumers. However, they
do not provide strong evidence to suggest that fruit
type is as important, but support promoted guidelines
encouraging fruit consumption for health in women. In
the case of stroke, a consistent, dose-response
association with tea consumption on both incidence
and mortality of stroke, being significative for tea when
high and low intakes were compared or the addition of
3 cups/d was estimated [410]. Most of prospective
studies have reported a weak inverse association
between moderate consumption of coffee and risk of
stroke. However, there are yet no clear biological
mechanisms whereby coffee might provide
cardiovascular health benefits [411]. In the REGARDS
study, a biracial prospective study, greater consumption
of flavanones, but not total or other flavonoid
subclasses, was inversely associated with incident
ischemic stroke. However, higher flavanone intake in
blacks suggests that flavanone intake is not implicated
in racial disparities in ischemic stroke incidence [412].
Over the last twenty to thirty years, numerous
pharmacologic agents have been evaluated to interrupt
the destructive pathophysiology of stroke and protect
the brain. Therapeutic strategies have included
minimizing the effects of excitatory amino acids,
blunting transmembrane calcium fluxes, and limiting
injury from inflammation, free radical damage, and
intracellular enzymes. Many of the early studies were
flawed by late administration of therapy within the
four-to-six hour therapeutic window for brain
reperfusion. In the majority of cases, treated subjects
experienced no benefit and, in some cases, outcomes
were worse than in control subjects. The reasons for
clinical failure of potentially favorable preclinical
therapies are multiple. Beyond the methodological
flaws in some clinical studies, it is important to
recognize that experimentally induced stroke in
animals does not mimic the heterogeneous nature of
human stroke. Furthermore, many animal studies do
not take into account the aging human brain of many
stroke patients. The only pharmacologic therapy to
receive a recommendation for use in current guidelines
is the hydroxymethylglutaryl co-enzyme A reductase
inhibitor (i.e., statins) [413]. The effect of EGCG in
extending the rt-PA treatment window in this clinical
trial among stroke patients was recently tested [414].
Patients were randomly assigned according to their
onset-to-treatment time (OTT) and were then treated
with rt-PA simultaneously with EGCG or placebo.
Administration of EGCG (500 mg/day) significantly
improved treatment outcomes of patients in the delayed
OTT strata, as evidenced by improved NIHSS scores.
This improved treatment outcome was likely attributed
to reduction in plasma levels of both MMP-2 and
MMP-9, as indicated by strong linear correlations
between both MMPs and NIHSS scores in all patients.
EGCG could potentially be used as a supplement of
traditional rt-PA treatment among stroke patients,
particularly those with delayed OTT, to extend the
otherwise narrow therapeutic window and improve the
outcome in late stroke treatment.
CONCLUSIONS
CVD, including coronary heart disease and
stroke, is the major cause of death worldwide,
especially in Western society. Flavonoids are a large
group of polyphenolic compounds widely distributed in
plants, present in considerable amount in fruit and
vegetable. Several epidemiological studies found an
inverse association between flavonoids intake and
mortality by CVD. In light of recent evidences, it is
possible to conclude that some specific flavonoids
(mainly flavonols and flavanols), in addition to their
antioxidant effect, modulate the activity of a number of
enzymes involved in biochemical signaling pathways
known to be involved in the pathophysiology of
ischemic heart disease and stroke. Thus, flavonoids
might prevent cardiovascular events acting by several
mechanisms, including reduction in the plasma levels
of glucose and fatty acids, LDL-oxidation, vascular
inflammation, endothelial dysfunction, vascular smooth
muscle growth and vascular remodeling, high BP,
coronary tone, plaque vulnerability, platelet
aggregation, and neurotoxicity.
In view of the great number of positive and
promising results, but also the number of unsolved
questions, such as the most useful flavonoid to prevent
CVD in humans, the ideal dose or daily intake, the
main mechanism of action, the pharmacokinetic
profile, the possible interaction with other natural
compounds or drugs, the long-term toxicity, etc., more
research is needed, with single or standardized
mixtures of flavonoids, using randomized, double-blind
control trials in a wide range of patients, to unravel the
complex mechanisms and effects of flavonoids on
cardiovascular protection.
CONFLICT OF INTEREST

Cardiovascular effects of flavonoids Current Medicinal Chemistry, 2018, Vol. 0, No. 0 23
The authors confirm that this articles content
has no conflicts of interest.
ACKNOWLEDGMENTS
This work was supported by Grants from
Comisión Interministerial de Ciencia y Tecnología,
Ministerio de Economía y competitividad (SAF2014-
55523-R), Junta de Andalucía (Proyecto de excelencia
P12-CTS-2722, and CTS 164) with funds from the
European Union, and by the Ministerio de Economia y
Competitividad, Instituto de Salud Carlos III (CIBER-
CV, CIBER-es), Spain. M.S. is a postdoctoral fellow of
Junta de Andalucía, and M.R. is a postdoctoral fellow
of University of Granada.
ABBREVIATIONS
AA = Arachidonic acid
ABCA1 = ATP-binding cassette transporter A1
ABCG1 = ATP-binding cassette transporter G1
ACE = Angiotensin-converting-enzyme
ADMA = Asymmetrical dimethylarginine
AMPK = AMP-activated protein kinase
AngII = Angiotensin-II
Akt = Protein kinase B
ARE = Antioxidant response elements
BAT = Brown adipose tissue
BBB = Blood-brain barrier
BH4 = Tetrahydrobiopterin
BMI = Body mass index
BP = Blood pressure
CAT = Catalase
Cav-1 = Caveolin-1
COMT = Catechol-O-methyltransferase
COX = Cyclooxygenase
CVD = Cardiovascular disease
Dab2 = Disabled 2
DASH = Dietary Approaches to Stop
Hypertension
DOCA = Deoxycorticosterone acetate
eNOS = Endothelial nitric oxide synthase
ER = Endoplasmic reticulum
ERK1/2 = Extracellular-signal-regulated
kinases 1/2
EGCG = Epigallocatechin gallate
ET-1 = Endothelin-1
FMO3 = Flavin-containing mono-oxygenase 3
GLUT = Glucose transporter
GCL = γ-glutamylcysteine ligase
GST = Glutathione-S-transferase
HbA1c = Glycated hemoglobin
HDL = High density lipoproteins
HFD = High fat diet
HIF = Hypoxia-induced factor
HO1 = Heme oxygenase-1
HUMSCs = Human umbilical cord mesenchymal
stromal cells
HUVECs = Human umbilical endothelial cells
ICAM-1 = Intercellular adhesive molecule
IL-1β = Interleukin-1 beta
IL-6 = Interleukin-6
iNOS = Inducible nitric oxide synthase
IP3 = Inositol (1,4,5)-trisphosphate
I/R = Ischemia/reperfusion
IR = Insulin receptor
IRS1 = Insulin receptor substrate 1
JNK = C-Jun N-terminal kinase
Keap-1 = Kelch-like ECH-associated protein 1
LDL = Low density lipoproteins
L-NAME = nitro-L-arginine methylester
LPS = lipopolysaccharide
MAPKs = Mitogen-activated protein kinases
MCP-1 = monocyte chemotactic protein-1
miRNAs = MicroRNAs
MMP = Metalloproteinase
mPTP = Mitochondrial permeability transition
pore
NAFL = Nonalcoholic fatty liver
NF-kB = Nuclear factor kappa-light-chain-
enhancer of activated B cells
NO = Nitric oxide
NQO1 = NADPH:quinone oxidoreductase 1
Nrf2 = Nuclear factor E2-related factor 2
OTT = Onset-to-treatment time
ox-LDL = oxidized LDL
p38MAPK = p38 mitogen-activated protein kinase
PI3-K = Phosphatidylinositol 3-kinase
PDE = Phosphodiesterases
PKG = Protein kinase G
PON = Paraoxonase
PPARγ = Peroxisome proliferator-activated receptor
gamma
Q3GA = Quercetin-3-glucuronide
REGARDS = REasons for Geographic and Racial
Differences in Stroke
ROS = Reactive oxygen species
rt-PA = Recombinant tissue plasminogen
activator
RWPs = Red wine polyphenols
sGC = Soluble guanylyl cyclase
SENP = SUMO-specific isopeptidases
SHR = Spontaneously hypertensive rats
SIRT-1 = Sirtuin 1
SOD = Superoxide dismutase
STZ = streptozotocin

24 Current Medicinal Chemistry, 2018, Vol. 0, No. 0 Sánchez et al.
SUMO = Small Ubiquitin-like MOdifier
TBI = Traumatic brain injury
TMA = Trimethylamine
TMAO = Trimethylamine N-oxide
TNF-α = Tumor necrosis factor alpha
TxA2 = Thromboxane A2
VCAM-1 = Vascular cell adhesive molecule-1
VEGF = Vascular endothelial growth factor
VSMCs = Vascular smooth muscle cells
WAT = White adipose tissue
WHO = World Health Organization
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