Sirt1 Inhibits Oxidative Stress in Vascular Endothelial Cells
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
Guangdong Key Lab of Shock and Microcirculation Research, Department of Pathophysiology, Southern Medical University,
Guangzhou 510515, China
Correspondence should be addressed to Zhongqing Chen; email@example.com
Received 18 January 2017; Revised 15 March 2017; Accepted 22 March 2017; Published 4 May 2017
Academic Editor: Silvana Hrelia
Copyright © 2017 Weijin Zhang et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The vascular endothelium is a layer of cells lining the inner surface of vessels, serving as a barrier that mediates microenvironment
homeostasis. Deterioration of either the structure or function of endothelial cells (ECs) results in a variety of cardiovascular
diseases. Previous studies have shown that reactive oxygen species (ROS) is a key factor that contributes to the impairment of
ECs and the subsequent endothelial dysfunction. The longevity regulator Sirt1 is a NAD
-dependent deacetylase that has a
potential antioxidative stress activity in vascular ECs. The mechanisms underlying the protective eﬀects involve Sirt1/FOXOs,
Sirt1/NF-κB, Sirt1/NOX, Sirt1/SOD, and Sirt1/eNOs pathways. In this review, we summarize the most recent reports in this
ﬁeld to recapitulate the potent mechanisms involving the protective role of Sirt1 in oxidative stress and to highlight the
beneﬁcial eﬀects of Sirt1 on cardiovascular functions.
The vascular endothelium lining the inner walls of vessels
has multiple functions such as maintaining microenviron-
ment homeostasis, nutrient exchange, host defense
reactions, and vasodilation . Endothelial damage is
secondary to a variety of stimuli and results in the loss
of endothelial integrity, barrier dysfunction, and abnormal
regulations of vasodilation and vasoconstriction, eventually
leading to alteration of the vascular environment .
Subsequently, this alteration causes changes in vascular
hemodynamics, aﬀects organ perfusion, and results in the
occurrence of cardiovascular events and a high incidence
of mortality . Therefore, great importance should be
attached to protecting the structure and functions of
microvascular endothelium. Reactive oxygen species
(ROS) is produced in lots of pathogenesis, such as diabetic
mellitus, asthma, and atherosclerosis, and ROS has been
considered to play a pivotal role in endothelial dysfunction
for decades [4–6]. When ECs are exposed to reactive
oxygen, a subsequent endothelial hyperpermeability occurs
and can result in various diseases such as acute respiratory
disease syndrome and asthma, due to ROS-related cascade
eﬀects. Plasma extravasation and bronchial hyperrespon-
siveness were reported to occur after exposure to H
inhalation . Therefore, amelioration of ROS-dependent
endothelial dysfunction represents a promising target to
delay the development of related diseases.
As a class III nicotinamide adenine dinucleotide- (NAD-)
dependent histone deacetylase, Sirt1 has been demonstrated
to regulate critical metabolic processes including oxidative
stress, ageing, and apoptosis via deacetylation of a variety of
substrates [8, 9]. Intriguingly, the inhibition of Sirt1 with
pharmacological agents or siRNA  leads to an elevation
of ROS levels, indicating a deﬁnite relationship between Sirt1
and ROS. However, the mechanisms underlying the Sirt1-
mediated ROS decrease remain obscure. In this report, the
interplay between Sirt1 and ROS will be elaborated. The
signaling networks of Sirt1 involved in ROS resistance are
shown in Figure 1.
Oxidative Medicine and Cellular Longevity
Volume 2017, Article ID 7543973, 8 pages
2. Molecular Biology, Function of Sirt1
It is widely acknowledged that silencing information regula-
tor complex (SIR complex) confers longevity for yeast .
In yeast, the SIR complex consists of four groups (Sir1-
Sir4), among which Sir2 has been veriﬁed to be widespread
in several types of cells . In mammals, there are seven
kinds of members (homologues of Sir2), which are termed
sirtuins. According to molecular analysis of conserved core
domain sequence of sirtuin from a variety of organs, the
seven sirtuins are classiﬁed into 4 groups. Group I includes
Sirt1, 2, and 3, group II includes Sirt4, group III includes
Sirt5, and group IV includes Sirt6 and 7 . Among these,
Sirt1 is the most extensively studied homologue due to its
similarity with Sir2 and its potential protective role in vascu-
lar disease. The gene encoding Sirt1 is located at 10q21.3, and
length is 33715 bp, with nine exons encoding 747 amino
acids, which includes 275 deacetylated amino acids located
in the core domain .
So far, several natural and synthetic substances have
been reported to activate Sirt1 and promote endothelial
homeostasis. Resveratrol is the most widely used. Resvera-
trol is a subtype of phytoalexins that protects ECs against
enhanced proinﬂammatory cytokines and reactive oxygen
[15–17]. Resveratrol has been proven to induce
mitochondrial biogenesis and promote vascular health
. Polydatin is another valuable ingredient extracted
from the roots of the traditional Chinese herb called
Polygonum cuspidatum. Our research team has validated
that polydatin protects hepatocytes , small intestines
, and kidney  against hemorrhagic shock by upreg-
ulating Sirt1 levels. Another active compound tetramethyl-
pyrazine (TMP) is isolated from a Chinese herb and is
capable of reversing high glucose-induced endothelial
dysfunction via upregulation of Sirt1 . Moreover,
Vitamin D could remarkably reverse endothelial damage
caused by oxidative stress, via Sirt1 activation .
Quercetin is a ﬂavonol compound and inhibits oxidized
LDL-induced EC damage, by activating Sirt1 . In addi-
tion, there are several other naturally polyphenols, for
instance, ﬁsetin and butein that activate Sirt1 .
By interacting with several target proteins, Sirt1 exerts a
wide range of cellular functions including energy balance,
lipid homeostasis, and especially, endothelial protection from
vascular diseases . In aging arteries, downregulation of
Sirt1 expression contributes to the formation of plaque
and foam cells, which are related with atherosclerosis
when endothelium is predisposed to attack. It has been
shown that phosphorylation of Sirt1 at serine 47 induced
by CDK5 activates Sirt1 and exerts antisenescence eﬀect
on vascular ageing . Zhang et al.  suggested that
Sirt1 expression should be controlled accurately for
regulating metabolism homeostasis and inﬂammatory
responses in order to delay or reverse the exacerbation of
atherosclerosis. Mice deﬁcient in Sirt1 had abnormal heart
development and a severely shorten life span, indicating
the pivotal role of Sirt1 in the maintenance of heart-
protective functions. These eﬀects of Sirt1 indicate that
Sirt1 has a great potential to emerge as an attractive can-
didate for the amelioration of endothelial dysfunction
. Additionally, Sirt1 activation induced by pulsatile ﬂow
prevents EC dysfunction and retards the progression of
atherosclerosis . Furthermore, Sirt1 is also indispensable
for the survival of cardiomyocytes, counteracting ischemia-
reperfusion injury and cardiac rhythm [31, 32]. This review
will discuss the molecular mechanisms of Sirt1 activation
and the eﬀect of Sirt1 on endothelial protection.
Functioning as an NAD
-dependent deacetylase, Sirt1
is capable of deacetylating numerous targets to protect
ECs . By deacetylating p53, Sirt1 may prevent stress-
induced senescence and dysfunction of ECs . Sirt1
could also promote proliferation and prolong senescence
by targeting LKB1 in ECs . Downregulation of
p66Shc expression through Sirt1 activation protects vessels
from hyperglycemia-induced EC dysfunction . Fur-
thermore, Sirt1 activator-induced mitochondrial biogenesis
in ECs is mediated by the upregulation of targets such as
proliferator-activated receptor gamma coactivator-1alpha
(PGC-1α), nuclear respiratory factor 1 (NRF1), and eNOs
. Ghisays has reported that the N-terminal domain of
Sirt1 enhanced its association with substrate NF-κB p65 in
the nucleus and decreased inﬂammation . Increase of
Sirt1 expression induced by resveratrol has been demon-
strated to diminish TNF-α-induced CD40 elevation in
human umbilical vein ECs (HUVECs) . It is also
widely acknowledged that Sirt1 deacetylase is an important
in vivo regulator of autophagy . Autophagy is activated
in response to diﬀerent kinds of stimuli by augmenting
stress resistance and clearance ability [39, 40]. Resveratrol
was reported to protect HUVECs from atherosclerosis by
upregulating Sirt1 levels, restoring lysosomal function,
enhancing autophagic ﬂux, and accelerating Ox-LDL
degradation through the autophagy-lysosome degradation
pathway . Taken together, the results of these studies
help to elucidate the mechanisms by which Sirt1 exerts
its protective eﬀect on ECs.
Figure 1: Signaling pathways of Sirt1 inhibiting reactive stress in
ECs. There is interplay between Sirt1 and FOXOs in ROS
reduction. Sirt1 also directly interacts with eNOs and SOD, which
could be regulated through FOXOs. NOX and NF-κB also serve as
downstream target of Sirt1, which could be downregulated by NF-
κB activation. These molecules play pivotal roles in reactive stress
resistance in ECs.
2 Oxidative Medicine and Cellular Longevity
3. Sirt1 Inhibits Oxidative Stress
Oxidative stress is characterized by the imbalance between
the ROS production and oxidative stress resistance .
ROS includes superoxide (O
), hydrogen peroxide (H
), and hypochlorite (OCl
). which partici-
pate crucially in the impairment of ECs. ROS plays a pivotal
role in many diseases including atherosclerosis, diabetic
mellitus, and myocardial dysfunction . There is extensive
interplay between reactive stress and Sirt1. Sirt1 has gained a
lot of attention for its role in oxidative stress resistance. The
mechanisms involved include Sirt1/FOXOs, Sirt1/NF-κB,
Sirt1/NOX, Sirt1/SOD, and Sirt1/eNOs pathways.
3.1. Sirt1 and FOXOs. FOXOs belong to a subgroup of Fork-
head family of transcriptional factors. Invertebrates possess
only one FOXO gene, whereas mammals have four FOXO
genes: FOXO1, FOXO3, FOXO4, and FOXO6 . In
response to stress, FOXOs translocate into the nucleus and
augment its protein expression, thus engaging in a variety
of cellular functions that regulate cell cycle, enhance cell
immunity, and inhibit oxidative stress. Evidence showed that
activation of FOXO3 could protect quiescent cells from oxi-
dative stress by directly binding to the manganese superoxide
dismutase (MnSOD) promoter and enhancing expression of
MnSOD to resist ROS . Conversely, FOXO inhibition
rendered a decrease in oxidative stress resistance and
increase in ROS level, indicating the pivotal role of FOXOs
in ROS resistance .
The link between FOXO and Sirt1 indicates an evolution-
arily mechanism for oxidative stress resistance. FOXO1,
FOXO3a, and FOXO4 are indispensable for Sirt1-
dependent cell survival against oxidative stress . It has
been shown that Sirt1 and FOXO3 formed a complex upon
stimulation with oxidative stress, and during both in vivo
and in vitro conditions, Sirt1 deacetylated FOXO3 to induce
resistance to oxidative stress . Sirt1 enhances FOXO1
DNA binding ability by deacetylating FOXO1 and attenuates
the oxidative stress response . Similarly, Sirt1 binds to
FOXO1 in an NAD-dependent manner and enables the accu-
mulation of FOXO4 in the nucleus, producing DNA damage-
inducible protein 45, a stress resistance-related gene .
However, the details of the interactions between FOXO1
and Sirt1 remain elusive for which one functions as upstream
of the other. It was noted that FOXO3a modulated Sirt1 tran-
scription by combing with p53 elements under nutrient
stress, suggesting that FOXO3a might modulate Sirt1 expres-
sion . Xiong et al.  indicated that FOXO1 directly
activated Sirt1 expression in vascular smooth muscle cells
and HEK293 cells. Overexpression of FOXO1 enhances
Sirt1 levels, indicating that FOXO1 is a positive regulator
of Sirt1. Intriguingly, Sirt1 activation can trigger FOXO1
deacetylation and augment FOXO-driven Sirt1 autotran-
scription. Therefore, autofeedback may participate in
FOXO1-dependent Sirt1 transcription and Sirt1-mediated
In spite of the obscure interactions between Sirt1 and
FOXO in response to oxidative stress, to a certain extent,
their interaction with each other, indeed, beneﬁts vascular
ECs. Evidence showed that Sirt1-dependent activation of
FOXO1 was crucial in vascular protection after the onset of
oxidative stress . Consistent with these results, a down-
regulation of Sirt1 and subsequent FOXO1-mediated
reduction of mitochondrial antioxidant enzyme was induced
by hyperglycemia, implying that Sirt1/FOXO1 axis might
facilitate antioxidant eﬀects in ECs . In addition, Sirt1
and FOXO1 are crucial for angiogenesis and miR-217 can
impair angiogenesis by inhibiting Sirt1 and FOXO1. In con-
trast, elevation of Sirt1 levels and FOXO1 deacetylation via
inhibition of miR-217 in ECs increases antioxidant eﬀects
and prevents endothelial dysfunction . Furthermore,
Sirt1-deacetylated FOXO1 and subsequent repression of the
antiangiogenic eﬀects is considered to be a key factor contrib-
uting to the delayed senescence of ECs and a limited ROS
accumulation in high glucose condition . Therefore,
crosstalk between Sirt1 and FOXO serves a crucial role in
3.2. Sirt1 and NF-κB. The transcriptional factor NF-κB com-
prises of ﬁve subgroups including RelA or P65, RelB, c-Rel,
p50/p105, and p52/p100, which remain quiescent because
they are attached to an inhibitory protein IκB. After IKK trig-
gers IκB phosphorylation and renders the degradation of IκB,
NF-κB is activated and translocates from cytosol to the
nucleus . NF-κB activation is closely related to reactive
oxygen generation and greatly contributes to endothelial dys-
function. Several studies have revealed that antioxidant genes
are under the control of NF-κB. Through regulation of NF-
κB at the transcriptional level, a dramatic increase in mRNA
levels for NF-κB was detected and oxidative stress was
induced after cadmium (Cd) exposure . Moreover, oxi-
dative stress could be induced through upregulation of ROS
during pathogenesis of retinopathies and NF-κB inhibitor
SN50 dramatically reduces ROS production, indicating that
oxidative stress is mediated by NF-κB .
However, this process can be reversed through Sirt1 acti-
vation. Resveratrol protects HUVECs against TNF-α-
induced injury through promoting Sirt1-induced repression
of NF-κB and ROS generation. The N-terminal domain of
Sirt1 is a positive regulator of the endogenous Sirt1-
dependent deacetylation capacity and promotes its physical
association with NF-κB p65 by deacetylating p65, thereby
inhibiting NF-κB transcription [16, 37]. In bovine retinal
capillary endothelial cells (BRECs), Sirt1 overexpression
inhibited the increase in mitochondrial reactive oxygen by
diminishing NF-κB expression while depletion of Sirt1 via
siRNA presented reduced resistance to ROS induced by
hyperglycemia stress . It has been shown that vascular
oxidative stress and NF-κB were attenuated in response to
caloric restriction (CR) in cultured coronary arterial endo-
thelial cells (CAECs). Intriguingly, sera obtained from CR
animals showed antioxidant eﬀects and NF-κB inactivation.
The aforementioned eﬀect was Sirt1 dependent . Fur-
thermore, NF-κBand Sirt1 could be involved in antagonistic
crosstalk during the regulation of ROS in ECs. Sirt1 inhibits
NF-κB by directly deacetylating the p65 subunit or activating
AMPK and PPARα, which inhibits the NF-κB pathway and
naturally suppresses ROS generation. Additionally, NF-κB
3Oxidative Medicine and Cellular Longevity
transcription suppresses Sirt1 activation through ROS pro-
duction . Taken together, the above ﬁndings indicate that
Sirt1 regulates NF-κB signaling and controls ROS attack, and
NF-κB itself could decrease Sirt1 levels to increase ROS
3.3. Sirt1 and NOX. NADPH oxidase (NOX) family consists
of several members including: NOX isoforms, two organizer
subunits (p47phox, NOXO1), two activator subunits
(p67phox, NOXA1), and two DUOX-speciﬁc maturation
factors (DUOXA1 and DUOXA2) . The members func-
tion in multiple ways, including killing harmful microorgan-
isms, regulating pH in the phagosome , transporting ions
, and reducing inﬂammation. However, NOX can
damage tissues and organs for their participation in ROS
production after catalyzing their substrate molecules.
Sirt1 participates in diminishing NOX production. It was
conﬁrmed that Sirt1 inhibition was engaged in upregulation
of NOX oxidase subunits, p22phox, and NOX4, eventually
leading to endothelial dysfunction due to O
[65, 66]. Meanwhile, quercetin-induced upregulation of Sirt1
enhances AMPK activity and decreases NADPH production,
thus suppressing the hyperglycemia-induced oxidant
damage in HUVECs. Therefore, the Sirt1/AMPK/NADPH
pathway participates in antioxidant eﬀects promoted by
quercetin . It has been shown that Sirt1 is a key player
in cellular senescence and is NAD
content induced by ROS tend to impair Sirt1 activ-
ity . However, increased activity of NOX may enhance
content and Sirt1 levels to induce oxidized state in
ECs. These eﬀects were explained by the moderate and
transient increase in ROS, which induced Sirt1 expression,
inconsistent with the ﬁndings that short-term H
treatment could enhance Sirt1 levels [68, 69]. Hence, an
agonistic relationship exists between NOX and Sirt1 at
low dose of reactive oxygen.
3.4. Sirt1 and SOD. SOD (superoxide dismutase), a group of
metal-containing enzymes, is characterized by their ability
to scavenge reactive oxygen species. SOD enzymes
comprise of 3 members, including SOD1 (cytoplasmic),
SOD2 (mitochondrial), and SOD3 (extracellular). SODs
have a pivotal role in oxidative stress resistance speciﬁcally
in liberating H
by binding to a superoxide anion with
their metal zipper. Deﬁciency or impairment of metals in
SODs including Cu-SOD, Zn-SOD, Ni-SOD, Mn-SOD,
and Fe-SOD contributes to oxidative stress directly .
Sirt1 has been shown to promote manganese superoxide
dismutase (MnSOD) expression and increase the oxidative
stress resistance in human retinal microvascular endothelial
cell (RMECs). Sirt1 potentiates FOXO3a activation by
deacetylating FOXO3a, which increases the transcription of
downstream genes such as MnSOD. Therefore, Sirt1/
FOXO/MnSOD may contribute to oxidative stress resistance
in ECs . Moreover, elevation of NAD
levels and Sirt1
expression was detected after nicotinamide mononucleotide
(NMN) treatment in thoracic aorta. These eﬀects were
accompanied by MnSOD enhancement, which was probably
modulated by Sirt1 to exert vascular antioxidant eﬀect .
Rapidly increasing prevalence of diabetic mellitus has been
posing great threat to public health worldwide because of
the resulting endothelial dysfunction induced by oxidative
stress. Studies have shown that MnSOD was signiﬁcantly
downregulated in the aortas of diabetic WT mice, whereas
endothelium-speciﬁc Sirt1 transgenic mice successfully
reversed the MnSOD decline, thereby indicating the pivotal
role of the Sirt1/MnSOD pathway in the inhibition of
hyperglycemia-induced endothelial dysfunction . Simi-
larly, MnSOD expression was elevated by resveratrol and
conferred antioxidative stress protection in CAECs, which
was diminished by Sirt1 knockdown and mimicked by Sirt1
overexpression . Therefore, the involvement of Sirt1 acti-
vation and subsequent SOD upregulation may ameliorate
endothelial oxidative stress.
3.5. Sirt1 and Endothelial Nitric Oxide Synthase (eNOs). NOs
families comprise of three groups including neuronal nitric
oxide synthase (nNOs) expressed in vascular smooth mus-
cle, inducible nitric oxide synthase (iNOs) present in blood
vessels under abnormal conditions, and endothelial nitric
oxide synthase (eNOs) prominently expressed in ECs
. eNOs makes great contributions to oxidative stress
resistance by producing nitric oxide (NO) and inhibiting
generation . The functions of eNOs are greatly
dependent of its cysteine residues. Under oxidative stress,
S-glutathionylation of eNOs occurs, accompanied by a
decrease in NO activity and an increase in O
Therefore, oxidative stress could abolish eNOs activity
through S-glutathionylation .
The relationship between Sirt1 and eNOs in the process
of defending oxidative stress has been reported extensively.
It was demonstrated that Sirt1 agonist SRT1720 exerted salu-
tary eﬀects on expression of eNOs thus protecting HUVECs
from senescence induced by H
. Furthermore, Sirt1 has
been shown to promote endothelium-dependent vasodila-
tion by targeting eNOs for deacetylation. Sirt1 and eNOs
colocalize in ECs, and subsequently, Sirt1 activates eNOs
through deacetylating lysine 496 and 506, and as a result,
NO production is increased. Consequently, its ability for
antioxidant stress is enhanced because NO bioavailability
is closely related to increased oxidative stress resistance
[76, 77]. Consistently, NO bioavailability was also veriﬁed
to be increased and was dependent on Sirt1-deacetylated
eNOs after pretreatment with docosahexaenoic acid .
In addition to deacetylating eNOs, Sirt1 has been demon-
strated to play a pivotal role in eNOs phosphorylation.
Inhibition of Sirt1 with Sirt1 siRNA decreased eNOs phos-
phorylation and abolished the protective eﬀects of curcum
-induced senescence in HUVECs, suggesting the
phosphorylation of eNOs by Sirt1 is a promising strategy
for combating premature senescence of HUVECs .
Intriguingly, Sirt1 was not absolutely the direct upstream of
eNOs. Evidence showed that Sirt1 could activate FOXOs to
synthesize antioxidants, and inhibition of Sirt1, FOXO1,
and FOXO3 attenuated the eﬀects of resveratrol on eNOs
activation, indicating that the Sirt1/FOXO axis is responsible
for eNOs elevation . In addition to the Sirt1/FOXO
pathway, eNOs and NO are produced and are induced in a
4 Oxidative Medicine and Cellular Longevity
Sirt1/Krüpple link factor 2 (KLF2)-dependent manner and
regulate endothelial function . Therefore, the interplay
between Sirt1 and eNOs serves as a salutary role in ROS
Although Sirt1 may be considered to be an optimal ther-
apeutic target for vascular diseases, discreet evaluations
should be conducted regarding the dosage to be used for
therapy. As reported, 2.5–7.5-fold overexpression of Sirt1
prevents heart from oxidative stress via Sirt1/FOXO axis
accompanied by the consumption of NAD
. If NAD
overconsumed due to higher levels of Sirt1, mitochondrial
biogenesis reduces and its stress resistance is reversed, sug-
gesting that the beneﬁcial eﬀect of Sirt1 can only be achieved
at low to moderate doses. Careful evaluation is needed to
determine therapeutic doses in clinical practice .
ROS causes progressive deterioration of the structure and
function of ECs. As an antioxidative stress molecule, Sirt1
has been identiﬁed and studied to determine its role in ROS
resistance in ECs. Intriguingly, transient increase of ROS
could induce Sirt1 which, in turn, causes a decrease in ROS.
However, high ROS levels diminish Sirt1 activation. The
explanation for these eﬀects may involve diﬀerent cellular
activities to counteract ROS. There is a complex signaling
network for Sirt1-mediated ROS reduction involving Sirt1/
FOXOs, Sirt1/NF-κB, Sirt1/NOX, Sirt1/SOD, and Sirt1/
eNOs. Among these factors, eNOs and SOD are downstream
of FOXO, which could also activate Sirt1 and trigger the sig-
naling pathway through positive feedback. Therefore, the
positive network of the several antioxidant molecules would
amplify the eﬀect to defend oxidative stress. However, Sirt1
also serves as a key target of NF-κB, whose transcription
suppresses Sirt1 activation, resulting in the increase in ROS
generation and a decrease in ROS scavenging. Furthermore,
antagonist eﬀect exists between SOD and NF-κB. Transacti-
vator of transcription (Tat)-SOD protein can hinder NF-κB
activation, defending the oxidation-driven atherosclerosis in
HUVECs . Together with this, SOD could also attenuate
NF-κB and reverse monolayer hyperpermeability induced by
release of hemoglobin with hemolysis . Activation of NF-
κB was suppressed by NOX inhibition in ECs, indicating the
interplay between NF-κB and NOX . The NOX/NF-κB
signaling was also shown to engage in aggravated endothelial
dysfunction due to high-dose intravenous iron supplementa-
tion . It has been shown that NOX2-p47phox complex is
formed to activate eNOs phosphorylation and NO produc-
tion in ECs exposed to laminar shear stress, whereas the
NOX1-NOXO1 complex could uncouple eNOs in the
condition of atherogenic oscillatory shear stress, thus injur-
ing ECs . Probably, diﬀerent submits of NOX may exert
diﬀerent eﬀects on ECs by interacting with eNOs. Therefore,
the downstream molecules of Sirt1 may interact with each
other as a network, to amplify the antioxidant eﬀect.
Despite the promising evidence, however, due to the fact
that excessive expression of Sirt1 seems to exert the opposite
eﬀect, appropriate upregulation of Sirt1 may be taken into
consideration for vascular disease therapy. Therefore, much
more studies in high quality should be carried out for Sirt1
elevation regarding the optimal dosage as therapeutic use
and its practical potential for disease prevention and protec-
tion in clinical application.
Conflicts of Interest
The authors declare that there are no conﬂicts of interest.
This work is supported by grants from the Natural
Science Foundation of Guangdong Province, China
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8 Oxidative Medicine and Cellular Longevity