Cardiovascular and Metabolic Effects of Açaí, an Amazon Plant

Abstract

Despite of being used for long time by Brazilian people that live on the Amazon bay, as food and beverages, only in the beginning of this century, açaí berries have been object of scientific research. Açaí berries are rich in polyphenols that probably explain its versatile pharmacological actions and huge consumption, not only in Brazil but also in Europe and United States. In this review, not all but some pharmacological aspects of acai berries are analysed. Chemical and pharmacological differences between extracts obtained from the skin and seed of acai are considered. Polyphenols from the seed of açaí increase endothelial NO production leading to endothelium-dependent relaxation, reduce reactive oxygen species and regulate key targets associated with lipid metabolism in different conditions such as hypertension, renal failure and metabolic syndrome. We review the novel mechanisms of actions of açaí on different targets that could trigger the health benefits of the açaí, such as antioxidant, vasodilator, antihypertensive, cardioprotector, renal protector, antidyslipidemic, antiobesity and antidiabetic effects in cardiovascular and metabolic disturbances.

Full text

INVITED REVIEW ARTICLE
Cardiovascular and Metabolic Effects of Ac¸aı
´,
an Amazon Plant
Roberto S. de Moura, MD, PhD and Ângela Castro Resende, PhD
Abstract: Despite being used for a long time as food and beverage
by Brazilian people who live on the Amazon bay, only in the
beginning of this century, açaí berries have been the object of sci-
entific research. Açaí berries are rich in polyphenols that probably
explains its versatile pharmacological actions and huge consumption,
not only in Brazil but also in Europe and United States. In this
review, not all but some pharmacological aspects of açaí berries
are analyzed. Chemical and pharmacological differences between
extracts obtained from the skin and seed of açaí are considered.
Polyphenols from the seed of açaí increase endothelial nitric oxide
production leading to endothelium-dependent relaxation, reduce
reactive oxygen species and regulate key targets associated with lipid
metabolism in different conditions such as hypertension, renal fail-
ure, and metabolic syndrome. We review the novel mechanisms of
actions of açaí on different targets which could trigger the health
benefits of açaí such as antioxidant, vasodilator, antihypertensive,
cardioprotector, renal protector, antidyslipidemic, antiobesity, and
antidiabetic effects in cardiovascular and metabolic disturbances.
Key Words: açaí, polyphenols, antioxidant, vasodilation, hyperten-
sion, metabolic syndrome
(J Cardiovasc PharmacolÔ2016;68:19–26)
INTRODUCTION
A significant number of drugs used in medicine are
molecules derived from plants. Between 1981 and 2010, 34%
of medicines approved by the United States Food and Drug
Administration were natural products or direct derivatives of
natural products.
1
Brazil has a huge biodiversity, including
approximately 50 thousands of vegetal species that can be
a significant resource of new medicines. The plant Euterpe
oleracea Mart, also known by the popular name of açaí is
a multicaule palm with up to 25 stems per clump. E. oleracea
Mart fruits (berries) are rounded, violet in color, diameter
about 13.3 mm, weighs approximately 2 g and comprehend
a violet pulp (617%) and a beige seed (683%) (Fig. 1).
2,3
It
is largely diffused in Amazon region, mainly in Para,
Amazonas, Maranhao, Tocantins, and Amapa states of Brazil,
and the pulp of E. oleracea has been used for many years by
Brazilian Indians and also by poor Amazonian communities,
not only as food but also in the treatment of various symp-
toms, mainly fever, tiredness, and pain.
4
Consumption of açaí
pulp has increased significantly in the last years, not only in
Brazil but also in Europe and United States, where it is called
a“super fruit”.
5
Açaí is used not only by food industry but
also by the cosmetics and pharmaceutical industries including
nutraceutics. The pulp of açaí is easily separated from the
seed by grinding the açaí berry with water and then freezing
until the day of use. The amount of water added to açaí will
determine the obtainment of a final liquid or sort of a concen-
trated açaí juice. Nowadays the aqueous extract pulp of açaí
berries is used to make juice, ice-cream, sweets, and many
kinds of food and beverages, and usually the seed of açaí is
discarded. Approximately 202.216 tons of açaí berries were
processed in Brazil in 2013.
6
Interestingly açaí consumption
has become very popular among young Brazilian people as an
energetic drink.
Pharmacological studies on açaí berries are recent and the
majority of them started in the beginning of last decade and were
mainly concentrated in the chemical composition and antioxi-
dant effect.
5,7,8
Since then, various pharmacological studies have
been performed with both pulp and\or seed extracts demonstrat-
ing the presence of important pharmacological effects. This
review discusses the recent studies on the pharmacology of
extracts of açaí pulp and\or seed, (not juice blend), mainly its
cardiovascular, renal, metabolic, and antioxidant actions.
PHYTOCHEMICAL COMPOSITION
Chemical analyses of açaí berry have shown that both
pulp and seed of açaí are rich in polyphenols. As suspected,
because of its purple color, the pulp of açaí berry is rich in
anthocyanins. Chromatographic analysis of açaí pulp
showed the presence of a significant amount of flavonoids,
where 2 anthocyanins, cyandin 3-glucoside, and cyanidin
3-rutinoside were found to be the most predominant. How-
ever, protocatechuicacid and epicatechin were also identified
as minor compounds.
5,7–9
Chemical composition of açaí pulp
has been extensively revised
3
and the content of polyphenols
in the hydroalcoholic extract of açaí seed and pulp, mea-
sured by analyzing for total phenol by Folin-Ciocalteau pro-
cedure
10
was approximately 25% and 18%, respectively.
11
Differently from the pulp, chemical analysis of hydroalco-
holic extract of açaí seed (ASE) showed the predominant
presence of catechin, epicatechin, and polymeric and oligo-
meric proanthocyanidins.
12,13
Received for publication August 27, 2015; accepted November 11, 2015.
From the Department of Pharmacology, Institute of Biology, State University
of Rio de Janeiro, Rio de Janeiro, Brasil.
Supported by the National Council of Scientific and Technological Devel-
opment (CNPq) and Rio de Janeiro State Research Agency (FAPERJ).
The authors report no conflicts of interest.
Reprints: Roberto S. de Moura, MD, PhD, Departamento de Farmacologia e
Psicobiologia, I.B., Universidade do Estado do Rio de Janeiro; Av.
28 de Setembro, 87, Rio de Janeiro, Brasil, 20 551-030 (e-mail:
robertosoaresdemoura@gmail.com).
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5

ANTIOXIDANT EFFECT
Since the first suggestion in the 1960 that reactive
oxygen species (ROS) could play an important role in the
pathophysiology of hypertension,
14
the number of studies
published in this subject has been increased significantly.
15
ROS is generated by multiple sources including nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase, mitochon-
dria, xantine oxidase, uncoupled endothelium-derived nitric
oxide (NO) synthase, cycloxygenase, and lipoxygenase dur-
ing the reduction of oxygen and include unstable free radicals
such as superoxide (O
2
2
) and nonfree radicals such as hydro-
gen peroxide (H
2
O
2
). O
2
2
the dominant initial ROS species is
a short-lived molecule that can subsequently undergo enzy-
matic dismutase to H
2
O
2
.O
2
2
can oxidize proteins and lipids
leading to different toxic reactions. H
2
O
2
can be further con-
verted to highly reactive hydroxyl radical that causes cardio-
vascular dysfunction.
15,16
Usually, oxidative stress occurs
when there is an imbalance between formation and neutrali-
zation of ROS by enzymatic antioxidants such as superoxide
dismutase (SOD), catalase (CAT), glutathione peroxidase
(GPx), thioredoxin, and peroxiredoxin, or nonenzymatic anti-
oxidants such as ascorbate, tocopherols, glutathione, bilirubin,
and uric acid.
15
Membrane and protein oxidative damage can
be evaluated by formation of products of lipid peroxidation
(malondialdehyde–MDA) and protein carboxylation. As ex-
pected, the presence of polyphenols in açaí berries suggests
a significant antioxidant action. Numerous scientific publica-
tions have demonstrated a significant antioxidant action of
extracts obtained from both pulp and seed of açaí berries.
The antioxidant effect of açaí, as observed with other flavo-
noids, may be due to a direct scavenging of free radicals,
decrease of endogenous ROS producing enzymes, and
increase of endogenous ROS scavenging enzymes
17
(Fig. 2).
Antioxidant capacity of açaí skin measured by total antioxi-
dant scavenging capacity assay, showed an excellent antiox-
idant capacity against peroxyl radicals, a good effect against
peroxynitrite, and poor against hydroxyl radicals.
8
The anti-
oxidant effect of açaí skin was confirmed by numerous other
studies, using different in vitro methodologies.
7,12,18,19
Studies
performed with health volunteers showed that açaí juice pre-
pared with the skin of the fruit induced an increase in plasma
antioxidant capacity of up to 3.3-fold.
20
Antioxidant capacity of açaí methanol and ethanol seed
extract showed a good antioxidant scavenging capacity against
peroxyl, peroxynitrite, and hydroxyl radicals.
12
This study also
demonstrated that the antioxidant scavenging capacity of açaí
seed against peroxyl radicals is in the same order of magnitude
as that of açaí skin, but more efficient against peroxynitrite and
hydroxyl radicals. The antioxidant effect of ASE may be due to
an in vivo action, because it induces activation of the endog-
enous antioxidant system through increase of SOD, CAT, and
GPx (Fig. 2). The antioxidant effect of ASE was demonstrated
in the isolated mesenteric vascular bed (MVB) of 2K-1C
hypertensive rats by decreasing MDA and carbonyl protein
levels and increasing the expressions of SOD, CAT and
GPx.
21
The increased levels of MDA and protein carbonylation
observed in mice that were fed a high-fat diet were prevented
by ASE.
22
Furthermore, oral treatment with ASE reduced oxi-
dative stress observed in adult rat offspring whose mothers
were fed a low protein diet during pregnancy.
23
CARDIOVASCULAR AND METABOLIC EFFECTS
Vasodilation
Since the demonstration by Furchgott and Zawadski
24
that the vasodilator effect of acetylcholine was dependent on
FIGURE 2. Cellular targets for ac¸aı
´and the corresponding
cardiovascular, renal, and metabolic effects. SREBP-1c, sterol-
regulatory-element binding protein-1c.
FIGURE 1. Euterpe oleracea Mart. (ac¸aı
´) palm tree, the rounded violet fruits and the seeds.
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5

the integrity of the endothelial cells—leading to the concept
that the cellular monolayer plays not only a simple passive
mechanical role but also an important control of blood vessel
functions
25,26
—compounds that modulate the endothelial
function have been the object of significant pharmacological
studies. Endothelial cells control vascular function by releas-
ing several autacoids such as NO, endothelium-derived hy-
perpolarizing factor, and prostaglandins which locally
modulate, among other functions, the vascular reactivity.
27
Control of vascular smooth muscle contractility by endothe-
lial cells is mainly modulated by NO, and the majority
of pathophysiological studies on this subject concentrate in
synthesis, release, and mechanism of action of NO on target
cells.
28
Release of NO by endothelial cells is a very complex
mechanism triggered by pharmacological and physiological
mechanisms such as activation of various receptors by neuro-
transmitters (acetylcholine and catecholamines), autacoids
(bradykinin, prostaglandins, histamine, angiotensin and sero-
tonin), and shear stress of the flowing blood on the endothe-
lial cells.
29
The production of NO is initiated by activation of 3
isoforms of NO synthase (NOS): neuronal (nNOS), inducible
(iNOS), and endothelial (eNOS). eNOS is constitutively and
mainly expressed in endothelial cells and synthesize NO in
a pulsatile Ca
2+
\calmodulin-dependent manner.
30,31
Once acti-
vated, the electrons donated by NADPH at the C-terminal
reductase domain are transferred to the heme catalytic center
of the N-terminal oxygenase domain, where activation of
molecular oxygen is “coupled”to NO synthesis by 2 succes-
sive mono-oxygenations of L-arginine.
32
The oxygenase
domain also binds an important eNOS cofactor tetrahydro-
biopterin (BH
4
) that plays an important role in the NO syn-
thesis. This cofactor promotes the assembly of eNOS
monomers into an active dimer and promotes electron transfer
to the N-terminal oxygenase domains of the other eNOS
monomer.
30,33,34
In some pathological situations (hyperten-
sion, atherosclerosis) where there is an increase in the forma-
tion of ROS induced mostly by stimulation of the NADPH
oxidase activity, BH
4
can be easily oxidized by ROS to dihy-
drobiopterin (BH
2
). As BH
2
cannot activate NO synthesis but
can compete with BH
4
by the N-terminal oxygenase domain
of eNOS, the formation of NO is reduced and O
2
2
is pro-
duced from the oxygenase domain, thereby converting eNOS
to a O
2
2
- producing enzyme, an uncoupled reaction,
30,35
that
contributes significantly to cardiovascular pathology. Impor-
tantly, BH
2
can be re-reduced to BH
4
by antioxidants such as
vitamin C.
36,37
eNOS activity can also be modulated by phosphoryla-
tion in several serine, threonine, and tyrosine residues.
Phosphorylation of serine 1177 residue induces activation
while threonine 495 residue induces inhibition of eNOS.
31
Phosphorylation of serine 1177, in the presence of Ca
2+
-cal-
modulin is activated by phosphorylated adenosine-
monophosphate-activated protein kinase (AMPK).
31,32,38,39
Therefore, compounds that induce phosphorylation of AMPK
may induce activation of eNOS. eNOS plays a very important
role in the control of normal cardiovascular function and
eNOS dysfunction has been extensively implicated in the
pathopysiology of various cardiovascular diseases, mainly
hypertension and atherosclerosis. Therefore, drugs that mod-
ulate eNOS activity may be important for the pharmacologi-
cal treatment of cardiovascular diseases.
As the majority of extracts of plants rich in polyphenols
induces vasodilation in isolated vessels,
40–42
it would be rea-
sonable to speculate that extracts from açaí skin and seed, that
contains significant amounts of flavonoids, would induce
a vasodilator effect. Indeed, extracts of the skin and açaí seed
induced a complete, dose-dependent, and long-lasting vaso-
dilator response in isolated MVB of the rat.
11
Interestingly,
the vasodilator potency expressed by ED
50
of both extracts,
demonstrated that the vasodilator effect of ASE (ED
50
= 1.11
60.4 mg) is significantly more potent than the extract from
the skin (ED
50
= 317.8 61.5 mg) of açaí berry.
11
Considering
that the concentration of polyphenols in skin (18%) and seed
(25%), are up to a certain point similar, the pharmacological
difference among those 2 extracts may be due to the chemical
differences of polyphenols occurring in the seed and in the
skin of açaí berry, as mentioned before.
The vasodilator effect of ASE in the MVB of the rat is
dependent on the integrity of the endothelium.
11
The
endothelial-dependent vasodilator response induced by ASE
is dependent on synthesis of NO, because it is significantly
reduced by L-NAME, an inhibitor of eNOS
43
(Fig. 2). The
vasodilator effect of ASE in the MVB of the rat may not be
due to the release of prostaglandins by the endothelial cells,
because the cyclo-oxygenase blocker indomethacin did not
alter the response.
11
The vasodilator effect of ASE is indepen-
dent of stimulation of muscarinic, histaminergic, alpha-2 adre-
noceptors, or bradykinin receptors at the level of endothelial
cells because treatment with atropine, pyrilamine, yohimbine,
or HOE 140, respectively, did not reduce the vasodilator
effect of ASE.
11
Endothelium-derived hyperpolarizing factor
may be involved in the mechanism of ASE vasodilation,
because the remaining portion of ASE-induced vasodilation
resistant to L-NAME, is almost completely abolished by com-
bination of L-NAME plus high potassium solution. Activation
of Ca
2+
-dependent K
+
, but not K
ATP
and Kv channels may
play an important role in the vasodilator effect of ASE
because it is inhibited by charybdotoxin plus apamin but
not by glybenclamide or 4-aminopyridine.
11
The contribution
of NO to the vasodilator effect of ASE is corroborated by the
demonstration that ASE induced an increase of NO formation
in cultured human umbilical vein endothelial cells that was
significantly reduced by L-NAME.
11
Interestingly, the extract
from the açaí pulp induces a significant inhibitory expression
of iNOS induced by LPS\II N-^
y in the cell culture of RAW
264 mouse monocyte-macrophages.
9
At the moment, the
mechanism of eNOS activation by ASE is not known, but
probably involves the participation of AMPK, because ASE
increases phosphorylation and activation of AMPK in dia-
betic rats (de Bem et al, unpublished data) and in mice treated
with high-fat diet (de Oliveira et al, submitted for publica-
tion), that may lead to phosphorylation of serine 321,177
residue, an important modulator of eNOS activation.
31–33,39
Hypertension
Incidence of hypertension is extremely high worldwide.
Close to 1 billion people suffer from this disease and the
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´
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5

mortality due to cardiovascular complication is very high.
44
Despite the large occurrence of hypertension, the leading
cause of morbidity and mortality worldwide, and the huge
number of papers published on hypertension, the pathophys-
iology of essential hypertension is not completely clear. The
theory that hypertension is due to deregulation of various
mechanisms that interact in the control of arterial blood pres-
sure, as proposed in the mosaic theory suggested by Irvine
Page (1949),
45
seems to be still valid. This concept helps us to
accept why pharmacological treatment of hypertension can be
performed by many drugs that have completely different
mechanisms of action. The consumption of fruits and vegeta-
bles has been shown to decrease the incidence of hypertension
and probably this effect is modulated by the presence of flavo-
noids occurring in the diet.
46
Antihypertensive effect of extracts
rich in polyphenols has been demonstrated by many pharma-
cological studies.
40,47,48
Because of its high content in poly-
phenols and an endothelium-dependent vasodilatation,
11
ASE
showed a significant antihypertensive effect in different types
of experimental hypertension rats (such as 2K-1C, deoxycor-
ticosterone acetate-Salt, spontaneously hypertensive rats and
L-nitro argenine methyl ester).
49,50
Antihypertensive action of ASE was further studied in
renovascular (2K-1C) hypertensive rats, a renin-dependent
hypertension.
21
This study demonstrated that ASE adminis-
tered orally prevented the increase in blood pressure and
plasma renin levels, recovered the endothelial-dependent
vasodilator effect of acetylcholine, increased nitrite content
and protein expression of eNOS, recovered SOD, CAT and
GPx activities, and decreased MDA and carbonyl protein
levels in the mesenteric vessels. This study also showed that
ASE decreased vascular structural changes induced by hyper-
tension because it reduced the increase in the media thickness
of the mesenteric and aortic arteries, and media to lumen ratio
in the aorta observed in nontreated hypertensive rats. Mor-
phological changes observed in SHR such as increase on
media thickness of the mesenteric and aortic arteries and
increase in the media to lumen ratio were also prevented by
treatment with ASE.
50
The mechanism of the antihypertensive
effect of ASE in 2K-1C and L-NAME hypertensive rats is not
completely elucidated, but probably an interaction between
NO and renin may play an important role (Fig. 2). Consider-
ing that NO induces an inhibitory effect on renin release by
juxtaglomerular cells,
51
an effect modulated by cyclic guano-
sine monophosphate-regulated protein kinase type II,
52
we
can speculate that reduction of renin release may be depen-
dent on the increase of NO activity induced by ASE. The
inhibitory action of ASE in renin release may also play an
important role in the antihypertensive action of ASE in L-
NAME hypertensive rats, because in this experimental model
of hypertension, the activation of renin-angiotensin system is
also present.
52–54
Considering that ASE increases phosphory-
lated AMPK (pAMPK) in diabetic rats (de Bem et al, unpub-
lished data) and in high-fat obese mice (de Oliveira et al,
submitted for publication), the reduction on plasma renin
concentration induced by ASE in 2K-1C hypertensive rat
and SHR
21,50
may be due to increase in pAMPK that has been
shown to control renin secretion.
55
However, the antihyper-
tensive effect of ASE may also involve mechanisms
independent of renin inhibition, because it was also demon-
strated in DOCA-Salt rats, a low-renin hypertension model.
49
Considering that adiponectin increases eNOS activity, and in
consequence NO production through AMPK-mediated phos-
phorylation of eNOS at Ser1177,
56
the beneficial effect of
ASE on endothelial dysfunction may also involve an interaction
of adiponectin and AMPK because ASE increases adiponectin
activity in diabetic rats (de Bem et al, unpublished data).
In SHR and 2K-1C models of experimental hyperten-
sion, there is a decrease in endothelial-dependent vasodilata-
tion induced by acetylcholine, characterizing the endothelium
dysfunction.
57
Considering that the equilibrium of blood flow
to the microcirculation is maintained largely by the endothe-
lium, disruption of this equilibrium can cause significant dam-
age to vascular homeostasis. Endothelium dysfunction at the
level of small arteries, the resistance vessels, can cause sig-
nificant physiological disturbances, as for instance, increase
in vascular resistance that may lead to arterial hypertension.
The mechanism of endothelial dysfunction observed in 2K-
1C and L-NAME hypertensive rats is very complex, but prob-
ably involves the increase in plasma angiotensin II that leads
to an increase in ROS formation, mainly depending on the
activation of NADPH oxidase.
58
The endothelial dysfunction
observed in 2K-1C and L-NAME hypertensive rats was abol-
ished by treatment with ASE.
21,50
Probably this effect may be
due to activation of eNOS through activation of adiponectin
activity,
56
phosphorylation of AMPK (de Bem et al, unpub-
lished data), and to an extent the antioxidant effect of ASE,
preventing oxidation of BH
4
.
The antihypertensive effect of açaí was studied not only
in anima vile but also in anima nobile. Hemodynamic effects
studied in a randomized, double-blinded, placebo-controlled
and crossover test in 20 normotensive healthy individuals
treated with 500 mg of açaí demonstrated a significant reduc-
tion in standing systolic blood pressure (24.6 69.3 mm Hg
vs. placebo 2.2 68.5 mm Hg) induced by açaí but no
changes were observed in other parameters (seated systolic
blood pressure, diastolic blood pressure, and electrocardio-
graphic parameters).
59
These results are similar to previous findings
60
that
showed no significant changes in systolic and diastolic blood
pressure or heart rate in normotensive overweight adults who
were treated with 100 g of açaí pulp twice daily for 1 month.
Those 2 studies differ from the data observed in rodents (see
above) because ASE induced a significant antihypertensive
effect in various models of experimental hypertension. This
discrepancy may be due to different kinds of extracts used in
those studies.
Myocardial Ischemia
Myocardial ischemia occurs when there is an imbalance
between the coronary blood supply and myocardial oxygen
demand. NO seems to play a very important role on
myocardial microcirculation, and endothelial dysfunction is
an independent prognostic factor for myocardial infarction.
61
During hypertensive crises demand for oxygen may be so
high that the offer cannot accomplish the oxygen need. Dur-
ing a constant oxygen demand by the myocardium, cardiac
ischemia can occur when there is abrupt reduction of oxygen
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offer to the myocardium, as happens during a short spasm
of the coronary arteries in Prinzmetal angina, or because of
an acute reduction of the coronary lumen due to rupture in
coronary atherosclerotic plaque and thrombus formation.
Therefore, pharmacological treatment of acute myocardial
infarction mainly includes drugs that increase coronary
blood flow and\or reduce myocardial oxygen demand. Con-
sidering that ASE induces vasodilation and reduction in
ROS, this extract may have a salutary action in myocardial
infarct. Indeed, a recent study demonstrated that oral treat-
ment with ASE induced an improvement of cardiac dys-
function (Fig. 2) and exercise intolerance in rats subjected
to experimental myocardial infarction.
62
Treatment with
ASE reversed the decrease in systolic arterial pressure, left
ventricular systolic pressure, left ventricular relaxation rate
and also reversed the increase in left ventricular end-
diastolic pressure, heart weight to body weight ratio
(cardiac hypertrophy), and left ventricular fibrosis observed
in rats subjected to myocardial infarction. These experimen-
tal results demonstrate a beneficial effect in delaying
cardiac remodeling and may indicate a possible ASE
administration to prevent heart failure resulting from
myocardial infarction.
Renal Failure
Preclinical data have shown a significant renal pro-
tective action of açaí skin extract in experimental renal
dysfunction. In glycerol-induced acute renal failure, açaí
treatment induced an improvement in kidney function such
as decrease in serum urea, creatinine, and blood urea nitro-
gen. The protective action of açaí is probably dependent on
its antioxidant action because renal oxidative stress
markers (renal catalase and reduced glutathione) were sig-
nificantly ameliorated by açaí
63
(Fig. 2). A beneficial effect
of açaí skin was also reported on renal ischemia\reperfu-
sion injury.
64
In this study, açaí produced a significant
attenuation of ischemia\reperfusion induced renal damage,
decrease of blood urea nitrogen levels, serum creatinine
and renal tissue content of kidney molecule-1, and also
reduction of MDA, myeloperoxidase, interferon-
g
, cas-
pase-3, collagen IV, and endothelin-1.
Numerous experimental studies have demonstrated the
association between small body weight at birth and later
cardiovascular disease, such as arterial hypertension.
65
This
association establishes a relationship between an adverse
intra-uterine or early postnatal nutritional environment and
development of disease in later life.
66
It has been shown that
offspring from rats that were protein restricted during preg-
nancy has lower than normal birth weight, and develop hyper-
tension in adulthood,
67,68
as well as, endothelial
dysfunction,
67
oxidative stress,
23,69
reduced nephron and glo-
merular number,
23,70
increased glomerular volume, increased
serum levels of renin, urea, creatinine and fractional excretion
of sodium.
23
All these functional and structural changes were
significantly prevented by oral administration of ASE during
pregnancy. Activation of oxidative stress, expressed by
increase in MDA and carbonyl protein levels and decrease
in SOD, CAT, and GPx expressions were prevented by ASE
treatment.
23
The beneficial effect of ASE may be related to
activation of eNOS\NO system that may correct the endothe-
lial dysfunction and inhibit renin plasma levels.
Metabolic Syndrome: Dyslipidemia and
Diabetes
Metabolic syndrome (MS), a progressive pathophysio-
logical state associated with substantially increased risk for
development of type 2 diabetes and atherosclerotic cardio-
vascular disease
71
is increasing worldwide. Among US adults
the prevalence of MS has been increasing significantly since
1999.
72
As pharmacological treatment of MS is mainly symp-
tomatic and is some time not successful, experimental studies
to develop new drugs to treat this highly prevalent syndrome
is worthwhile. Beneficial effects of açaí have been demon-
strated in experimental models of MS, and in healthy over-
weight adults.
2,22,60
Rats that were fed a hypercholesterolemic
diet presented increased levels of total and non–high-density
lipoprotein cholesterol and decreased levels of high-density
lipoprotein cholesterol.
73
The supplementation of diet with
açaí pulp caused a hypocholesterolemic effect by reducing
total and non–high-density lipoprotein cholesterol.
73
In mice subjected to a high-fat diet, the increase in body
weight, plasma triglycerides, total cholesterol, glucose levels,
oral glucose tolerance test, and insulin resistance (HOMA
index) were significantly reduced by oral ASE treatment.
22
As
previously demonstrated,
74
the vasodilator response to acetyl-
choline, but not to nitroglycerine was reduced in mice sub-
jected to high-fat diet, and the endothelial dysfunction was
prevented by ASE.
22
The possible molecular mechanisms
involved in the dyslipidemic effect of ASE were recently inves-
tigated (de Oliveira et al, submitted for publication). This study
showed that the reduction of pAMPK expression in the liver of
mice subjected to a high-fat diet is prevented by oral adminis-
tration of ASE. The increase in pAMPK by ASE is probably
one of the most important mechanisms of the beneficial effect
of ASE on the dyslipidemic state induced by high-fat diet,
because this protein modulates important steps on the lipid
metabolism. pAMPK induces phosphorylation and consequent
inhibition of acetyl-CoA carboxilase that catalyzes the carbox-
ylation of acetyl-CoA to form malonyl-CoA, an intermediate
metabolite that plays a key role in the regulation of fatty acid
metabolism.
75,76
Another important finding observed in mice
that were fed a high-fat diet is the increase in 3-hydroxy-3-
methylglutaryl CoA reductase (HMG-CoA-R), an important
factor that activates cholesterol synthesis (de Oliveira et al,
submitted for publication). The activity of HMG-CoA-R is
modulated by AMPK which in its phosphorylated and active
state induces inactivation of HMG-CoA-R.
77
The decrease in
pAMPK expression observed in mice that were fed a high-fat
diet may explain the increase in HMG-CoA-R expression
(Fig. 2). Consequently, the activation of AMPK by ASE
decreased HMG-CoA-R activity, an important mechanism of
the beneficial effect of ASE on altered lipid profile.
Lipid homeostasis is also regulated by sterol regulatory
element binding proteins that directly activate the expression of
over 10 genes involved in both the synthesis and uptake of
cholesterol, fatty acids, triglycerides, and phospholipids.
78
The
increase of sterol regulatory element binding proteins-1c
J Cardiovasc PharmacoläVolume 68, Number 1, July 2016 Cardiovascular and Metabolic Effects of Ac¸aı
´
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5

expression, an activator of genes involved in fatty acid synthe-
sis, observed in mice that were fed a high-lipid diet, was
reduced by treatment with ASE (de Oliveira et al, submitted
for publication) (Fig. 2). The beneficial antidyslipidemic effect
of ASE in mice that were fed a high-fat diet may not only be
due to decrease in cholesterol synthesis but also decrease in
absorption and increase in removal of excess of cholesterol
from the body. These mechanisms are modulated by ATP-
biding cassette, subfamily G transporters (ABCG) that induces
efflux of unesterified cholesterol from the enterocyte back to
the intestinal lumen, and biliary cholesterol secretion.
79
Indeed,
extracts from the seed and also from the skin of açaí induced an
over-expression of ABCG transporters, ABCG5 and ABCG8,
in rats that were fed a high-cholesterol diet
2
and also in mice
that were fed a high-fat diet (de Oliveira et al, submitted for
publication) (Fig. 2). Another interesting finding is the
improvement induced by ASE on hepatic steatosis induced
in mice that were fed a high-fat diet (de Oliveira et al, sub-
mitted for publication). Probably, these actions play an impor-
tant role on the beneficial effect of açaí extracts in the
cholesterol homeostasis. However, in a study performed in
mice that received a high-fat diet, a freeze dried açaí powder
did not reduce body weight gain, insulin blood levels, HOMA-
IR index, dyslipidemia, and in contrast, developed large stea-
totic livers.
80
Epidemiological studies have shown that world is facing
a pandemic of type 2 diabetes mellitus. Reports from the
International Diabetes Federation stated an estimation of 285
million people worldwide who had already been diagnosed
with diabetes, and the prevalence of diabetes in 2030 may
reach 450 million.
81,82
Therefore, research looking for new
compounds to treat diabetes is mandatory, and natural products
may be an important source for new therapy. Interestingly,
metformin, a biguanide compound, considered the first-
choice drug and the “gold standard”for most people with type
2 diabetes, developed from a herbal source, is derived from
galegine, which is naturally found in Gallega oficinalis (French
lilac, Goat’s rue; Italian fitch–Spanish sainfoin). AMPK, a key
modulator of body glucose homeostasis is an important target
of antidiabetic drugs. Activation of AMPK results in the stim-
ulation of glucose uptake in muscle, fatty acid oxidation, and
inhibition of hepatic glucose production, cholesterol and tri-
glyceride synthesis, and lipogenesis.
83
Recently, the beneficial
metabolic actions of ASE have been studied in rats with type 2
diabetes (de Bem et al, unpublished data). This study demon-
strated that oral treatment of diabetic rats with ASE reversed
the increase in glucose and insulin levels, HOMA index,
insulin receptor, hosphorylated c-Jun N-terminal kinase and
decrease in HOMA
b
, nitrites, expression of phosphorylated
insulin receptor substrate-1, phosphorylated protein kinase B,
adiponectin in adipose tissue, and glucose transporter-4. Prob-
ably these beneficial effects of ASE in type 2 diabetic rats is
dependent on AMPK because the increase in AMPK and
decrease in pAMPK observed in adipose tissue were reversed
by ASE (de Bem et al, unpublished data). The mechanism of
the antidiabetic effect of ASE is not known but it may be
modulated by NO release induced by ASE, because it has been
shown that the activation of AMPK by metformin is reduced
by inhibition of NO synthesis by L-NAME.
83
CONCLUSIONS
Analyses of the scientific information on açaí show that
the berries of this plant have significant pharmacodynamic
activities. Hydroalcoholic extract of açaí seed has a signifi-
cant antioxidant action, endothelial-dependent vasodilator
effect, and antihypertensive, antidiabetic, antiobesity, car-
diovascular, and renal protective effects. Probably these ac-
tions depend on the high concentration of polyphenols in the
skin and seed of açaí, that interestingly are different in ac-
tions, and in polyphenols concentration and composition.
The effects of açaí are dependent on stimulation of eNOS,
phosphorylation of AMPK, adiponectin activation, and
decrease of oxidative stress. Those pharmacological effects
support the conclusion that açaí extracts may have a benefi-
cial action in patients with MS.
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