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Sirt1 Inhibits Oxidative Stress in Vascular Endothelial Cells


Abstract and Figures

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- κ B, 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.
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Review Article
Sirt1 Inhibits Oxidative Stress in Vascular Endothelial Cells
Weijin Zhang,
Qiaobing Huang,
Zhenhua Zeng,
Jie Wu,
Yaoyuan Zhang,
Zhongqing Chen
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;
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 eects 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
eld to recapitulate the potent mechanisms involving the protective role of Sirt1 in oxidative stress and to highlight the
benecial eects of Sirt1 on cardiovascular functions.
1. Introduction
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 [1]. 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 [2].
Subsequently, this alteration causes changes in vascular
hemodynamics, aects organ perfusion, and results in the
occurrence of cardiovascular events and a high incidence
of mortality [3]. 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 [46]. 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
eects. Plasma extravasation and bronchial hyperrespon-
siveness were reported to occur after exposure to H
inhalation [7]. 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 [10] leads to an elevation
of ROS levels, indicating a denite 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 [11].
In yeast, the SIR complex consists of four groups (Sir1-
Sir4), among which Sir2 has been veried to be widespread
in several types of cells [12]. 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 classied 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 [13]. 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 [14].
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 proinammatory cytokines and reactive oxygen
[1517]. Resveratrol has been proven to induce
mitochondrial biogenesis and promote vascular health
[18]. 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 [19], small intestines
[20], and kidney [21] 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 [22]. Moreover,
Vitamin D could remarkably reverse endothelial damage
caused by oxidative stress, via Sirt1 activation [23].
Quercetin is a avonol compound and inhibits oxidized
LDL-induced EC damage, by activating Sirt1 [24]. In addi-
tion, there are several other naturally polyphenols, for
instance, setin and butein that activate Sirt1 [25].
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 [26]. 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 eect
on vascular ageing [27]. Zhang et al. [28] suggested that
Sirt1 expression should be controlled accurately for
regulating metabolism homeostasis and inammatory
responses in order to delay or reverse the exacerbation of
atherosclerosis. Mice decient 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 eects of Sirt1 indicate that
Sirt1 has a great potential to emerge as an attractive can-
didate for the amelioration of endothelial dysfunction
[29]. Additionally, Sirt1 activation induced by pulsatile ow
prevents EC dysfunction and retards the progression of
atherosclerosis [30]. 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 eect of Sirt1 on endothelial protection.
Functioning as an NAD
-dependent deacetylase, Sirt1
is capable of deacetylating numerous targets to protect
ECs [33]. By deacetylating p53, Sirt1 may prevent stress-
induced senescence and dysfunction of ECs [34]. Sirt1
could also promote proliferation and prolong senescence
by targeting LKB1 in ECs [35]. Downregulation of
p66Shc expression through Sirt1 activation protects vessels
from hyperglycemia-induced EC dysfunction [36]. 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
[18]. Ghisays has reported that the N-terminal domain of
Sirt1 enhanced its association with substrate NF-κB p65 in
the nucleus and decreased inammation [37]. Increase of
Sirt1 expression induced by resveratrol has been demon-
strated to diminish TNF-α-induced CD40 elevation in
human umbilical vein ECs (HUVECs) [16]. It is also
widely acknowledged that Sirt1 deacetylase is an important
in vivo regulator of autophagy [38]. Autophagy is activated
in response to dierent 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 ux, and accelerating Ox-LDL
degradation through the autophagy-lysosome degradation
pathway [15]. Taken together, the results of these studies
help to elucidate the mechanisms by which Sirt1 exerts
its protective eect on ECs.
oxidative stress
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 [41].
ROS includes superoxide (O
), hydrogen peroxide (H
hydroxide (OH
), 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 [42]. 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 [43]. 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 [44]. Conversely, FOXO inhibition
rendered a decrease in oxidative stress resistance and
increase in ROS level, indicating the pivotal role of FOXOs
in ROS resistance [45].
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 [46]. 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 [47]. Sirt1 enhances FOXO1
DNA binding ability by deacetylating FOXO1 and attenuates
the oxidative stress response [48]. 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 [49].
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 [50]. Xiong et al. [51] 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
FOXO1 deacetylation.
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, benets vascular
ECs. Evidence showed that Sirt1-dependent activation of
FOXO1 was crucial in vascular protection after the onset of
oxidative stress [52]. 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 eects in ECs [53]. 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 eects
and prevents endothelial dysfunction [54]. Furthermore,
Sirt1-deacetylated FOXO1 and subsequent repression of the
antiangiogenic eects is considered to be a key factor contrib-
uting to the delayed senescence of ECs and a limited ROS
accumulation in high glucose condition [55]. Therefore,
crosstalk between Sirt1 and FOXO serves a crucial role in
ROS resistance.
3.2. Sirt1 and NF-κB. The transcriptional factor NF-κB com-
prises of ve 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 [56]. 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 [57]. 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 [58].
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 [59]. 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 eects and NF-κB inactivation.
The aforementioned eect was Sirt1 dependent [60]. 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 [61]. Taken together, the above ndings 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-specic maturation
factors (DUOXA1 and DUOXA2) [62]. The members func-
tion in multiple ways, including killing harmful microorgan-
isms, regulating pH in the phagosome [63], transporting ions
[64], and reducing inammation. 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
conrmed 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 eects promoted by
quercetin [24]. It has been shown that Sirt1 is a key player
in cellular senescence and is NAD
-dependent. Decreases
in NAD
content induced by ROS tend to impair Sirt1 activ-
ity [67]. However, increased activity of NOX may enhance
content and Sirt1 levels to induce oxidized state in
ECs. These eects were explained by the moderate and
transient increase in ROS, which induced Sirt1 expression,
inconsistent with the ndings 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 specically
in liberating H
by binding to a superoxide anion with
their metal zipper. Deciency or impairment of metals in
SODs including Cu-SOD, Zn-SOD, Ni-SOD, Mn-SOD,
and Fe-SOD contributes to oxidative stress directly [41].
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 [70]. Moreover, elevation of NAD
levels and Sirt1
expression was detected after nicotinamide mononucleotide
(NMN) treatment in thoracic aorta. These eects were
accompanied by MnSOD enhancement, which was probably
modulated by Sirt1 to exert vascular antioxidant eect [71].
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 signicantly
downregulated in the aortas of diabetic WT mice, whereas
endothelium-specic 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 [72]. 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 [17]. 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
[73]. eNOs makes great contributions to oxidative stress
resistance by producing nitric oxide (NO) and inhibiting
generation [74]. 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 [75].
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 eects 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 veried
to be increased and was dependent on Sirt1-deacetylated
eNOs after pretreatment with docosahexaenoic acid [78].
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 eects of curcum
on H
-induced senescence in HUVECs, suggesting the
phosphorylation of eNOs by Sirt1 is a promising strategy
for combating premature senescence of HUVECs [79].
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 eects of resveratrol on eNOs
activation, indicating that the Sirt1/FOXO axis is responsible
for eNOs elevation [80]. 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 [81]. 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, 2.57.5-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 benecial eect of Sirt1 can only be achieved
at low to moderate doses. Careful evaluation is needed to
determine therapeutic doses in clinical practice [4].
4. Conclusion
ROS causes progressive deterioration of the structure and
function of ECs. As an antioxidative stress molecule, Sirt1
has been identied 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 eects may involve dierent 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 eect 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 eect 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 [82]. Together with this, SOD could also attenuate
NF-κB and reverse monolayer hyperpermeability induced by
release of hemoglobin with hemolysis [83]. Activation of NF-
κB was suppressed by NOX inhibition in ECs, indicating the
interplay between NF-κB and NOX [84]. The NOX/NF-κB
signaling was also shown to engage in aggravated endothelial
dysfunction due to high-dose intravenous iron supplementa-
tion [85]. 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 [86]. Probably, dierent submits of NOX may exert
dierent eects on ECs by interacting with eNOs. Therefore,
the downstream molecules of Sirt1 may interact with each
other as a network, to amplify the antioxidant eect.
Despite the promising evidence, however, due to the fact
that excessive expression of Sirt1 seems to exert the opposite
eect, 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 conicts of interest.
This work is supported by grants from the Natural
Science Foundation of Guangdong Province, China
(2016A030313561 and 2016A030310389).
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8 Oxidative Medicine and Cellular Longevity
... Being a cardioprotective gene, SIRT1 plays significant roles in regulation of angiogenesis, prevention of endothelial dysfunction and malicious effects of ischemiareperfusion injury [6,7]. It increases the DNA stability by binding and deactivating several substrates at a molecular level; regulates the expression of endothelial nitric oxide synthase (eNOS) and manganese superoxide dismutase (MnSOD) and activates the FoxO1 dependent pathways [8,9]. The patients that suffer from prior myocardial infarction or CAD are often seen to have increased levels of SIRT1 which is a result of compensatory mechanism for eliminating hazardous effects of oxidative stress and hypoxia [10]. ...
... According to transgenic rat study, researchers have discovered that SIRT1 is acting as dose-dependent pathway in heart. For example, moderate increase of SIRT1 preserves cardiomyocytes, and an extreme elevation in SIRT1 levels decreases cardiac function resulting in cardiomyopathy [9]. In another study, Sun et al. [44] observed that patients with atrial fibrillation show increase in SIRT1 expression. ...
... In another study, Sun et al. [44] observed that patients with atrial fibrillation show increase in SIRT1 expression. Alcendor et al. [9] demonstrated that increased SIRT1 expression of 2,5-to-7,5-fold decrease age dependent cardiac hypertrophy, apoptosis, cardiac dysfunction and expression of aging markers; however, 12,5-fold increase in SIRT1 expression causes oxidative stress, apoptosis and increased cardiac hypertrophy. CONCLUSION SIRT1 helps to prevent endothelial dysfunction and reperfusion injury due to ischemia. ...
Full-text available
One of the main causes of vessel injury in CAD is endothelial dysfunction proceeding with increased inflammation and increase in monocyte count. SIRT1 (sirtuin1) plays a vital role in regulation of cellular physiological mechanisms. SIRT1 helps in regulation of angiogenesis, preventing endothelial dysfunction and reperfusion injury due to ischemia. As a result of SIRT1 suppression, monocyte affinity is caused due to endothelial dysfunction. Pathology of many diseases involves Sirtuin activators and provides promising treatments. The objective of this review is to summarize the current progress and future directions of Sirtuin protein in the field of CAD.
... Sirtuins, a class III nicotinamide adenine dinucleotide-(NAD-) dependent histone deacetylase, owns seven members in mammals (SIRT1-7). Among them, silent mating type information regulation 2 homolog 1 (SIRT1) is a very important member and plays a critical role in metabolic syndromes, oxidative stress, inflammation, and aging (Yu and Auwerx, 2010;Zhang et al., 2017). It plays a key role in regulating endothelial functions and CVDs (Potente et al., 2007). ...
... It plays a key role in regulating endothelial functions and CVDs (Potente et al., 2007). The cardioprotective role of SIRT1 was related to the regulation of several pathways, such as SIRT1/FOXOs, SIRT1/NF-κB, SIRT1/Nox, SIRT1/-SOD, and SIRT1/eNOs (Zhang et al., 2017). NADPH oxidase isoforms (Noxs) family is a major source of ROS generation, among which Nox4 was highly expressed in cardiovascular tissues (Chen et al., 2012). ...
Full-text available
Oxidative stress is a potential factor in the promotion of endothelial dysfunction. In this research, flavonoids (quercetin, luteolin) combined with carotenoids (lycopene, lutein), especially quercetin-lycopene combination (molar ratio 5:1), prevented the oxidative stress in HUVEC cells by reducing the reactive oxygen species (ROS) and suppressing the expression of NADPH oxidase 4 (Nox4), a major source of ROS production. RNA-seq analysis indicated quercetin-lycopene combination downregulated inflammatory genes induced by H2O2, such as IL-17 and NF-κB. The expression of NF-κB p65 was activated by H2O2 but inhibited by the quercetin-lycopene combination. Moreover, the quercetin and lycopene combination promoted the thermostability of Sirtuin 1 (SIRT1) and activated SIRT1 deacetyl activity. SIRT1 inhibitor EX-527 attenuated the inhibitory effects of quercetin, lycopene, and their combination on the expression of p65, Nox4 enzyme, and ROS. Quercetin-lycopene combination could interact with SIRT1 to inhibit Nox4 and prevent endothelial oxidative stress, potentially contributing to the prevention of cardiovascular disease.
... Silent information regulator 2 (SIR2) proteins, also known as Sirtuins, first sparked interest in 1999, and was identified to modulate lifespan of yeast in Saccharomyces cerevisiae (Lu et al. 2018). Sirtuins are found in all aerobic organisms (Zhang et al. 2017b, a). For example, in mammals, seven human SIR2 homologues including SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7 have been identified ). ...
... Moreover, the deacetylation of FOXO is inhibited by the inhibitor of SIRT1, and SIRT1 mediated FOXO deacetylation could affect the cell survival (Wątroba et al. 2012). Meanwhile, activation of FOXO directly binds to the manganese superoxide dismutase (MnSOD) promoter, which significantly enhances MnSOD's ability to resist ROS, thereby protecting resting cells from oxidative stress (Zhang et al. 2017b, a). For example, resveratrol increased SOD2 levels, reduced ROS levels, and promoted cell survival through FOXO in C2C12 cells (Hori et al. 2013). ...
Full-text available
A significant amount of evidence from the past few years has shown that Sirtuin 1 (SIRT1), a histone deacetylase dinucleotide of nicotinamide adenine dinucleotide (NAD+) is closely related to the cerebral ischemia. Several potential neuroprotective strategies like resveratrol, ischemia preconditioning, and caloric restriction exert their neuroprotection effects through SIRT1-related signaling pathway. However, the potential mechanisms and neuroprotection of SIRT1 in the process of cerebral ischemia injury development and recovery have not been systematically elaborated. This review summarized the the deacetylase activity and distribution of SIRT1 as well as analyzed the roles of SIRT1 in astrocytes, microglia, neurons, and brain microvascular endothelial cells (BMECs), and the molecular mechanisms of SIRT1 in cerebral ischemia, providing a theoretical basis for exploration of new therapeutic target in future.
... Upregulation of SIRT1 exhibits direct inhibition of virus replication, followed by a decline in proinflammatory cytokine production, IL-1β, IL-6, and TNF-α, whereas downregulation of SIRT1 enhances replication of the viruses, causing an uncontrolled surge of proinflammatory cytokines [122], in a similar manner to that in the cytokine storm. Finally, SIRT1 activation remarkably inhibits oxidative stress [137,138] in vascular endothelial cells [139] that are heavily involved in the pathogenesis of the cytokine storm in COVID-19, knowing that hyperinflammation-induced uncontrolled oxidative stress results in substantial endothelial cell damage [8-10, 12, 13], capillary leak and edema 13 Oxidative Medicine and Cellular Longevity The effects of renalase deficiency in knockout mice with cisplatininduced AKI (in vivo) and the outcome of renalase administration in HK-2 against cisplatin and oxidant damage (in vitro). ...
Full-text available
The hallmark of the coronavirus disease 2019 (COVID-19) pathophysiology was reported to be an inappropriate and uncontrolled immune response, evidenced by activated macrophages, and a robust surge of proinflammatory cytokines, followed by the release of reactive oxygen species, that synergistically result in acute respiratory distress syndrome, fibroproliferative lung response, and possibly even death. For these reasons, all identified risk factors and pathophysiological processes of COVID-19, which are feasible for the prevention and treatment, should be addressed in a timely manner. Accordingly, the evolving anti-inflammatory and antifibrotic therapy for severe COVID-19 and hindering post-COVID-19 fibrosis development should be comprehensively investigated. Experimental evidence indicates that renalase, a novel amino-oxidase, derived from the kidneys, exhibits remarkable organ protection, robustly addressing the most powerful pathways of cell trauma: inflammation and oxidative stress, necrosis, and apoptosis. As demonstrated, systemic renalase administration also significantly alleviates experimentally induced organ fibrosis and prevents adverse remodeling. The recognition that renalase exerts cytoprotection via sirtuins activation, by raising their NAD+ levels, provides a “proof of principle” for renalase being a biologically impressive molecule that favors cell protection and survival and maybe involved in the pathogenesis of COVID-19. This premise supports the rationale that renalase’s timely supplementation may prove valuable for pathologic conditions, such as cytokine storm and related acute respiratory distress syndrome. Therefore, the aim for this review is to acknowledge the scientific rationale for renalase employment in the experimental model of COVID-19, targeting the acute phase mechanisms and halting fibrosis progression, based on its proposed molecular pathways. Novel therapies for COVID-19 seek to exploit renalase’s multiple and distinctive cytoprotective mechanisms; therefore, this review should be acknowledged as the thorough groundwork for subsequent research of renalase’s employment in the experimental models of COVID-19.
Although several recent studies have shown that vitamin D supplementation beneficially decreases oxidative stress parameters, there is no consensus on this subject in humans. Thus the role of vitamin D supplementation has recently become a controversial topic because large intervention studies in humans have not shown significant benefits. These studies have indicated that supplementation with precursor forms of active vitamin D has no effect on all-cause mortality, cannot reduce the fracture risk of the elderly, cannot reduce the incidence of cancer or cardiovascular disease in the elderly, and cannot significantly reduce the incidence risk of diabetes in the elderly. However, a link between several age-related diseases and enhanced oxidative stress has been found in mice with insufficient or deficient 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D, which indicates that reduced active vitamin D accelerates aging and age-related diseases by increasing oxidative stress. Furthermore, supplementation of exogenous 1,25(OH)2D3, or antioxidants, could dramatically postpone aging, prevent osteoporosis and spontaneous tumor development induced by 1,25(OH)2D insufficiency or deficiency, by inhibiting oxidative stress. Mechanistically, the antioxidative effects of 1,25(OH)2D3 are carried out via the vitamin D receptor (VDR) by activation of the Nrf2 oxidative stress response pathway though transcriptional or posttranscriptional activation of Nrf2 or transcriptional upregulation of Sirt1 and Bmi1 expression. Whether discrepancies between studies in humans and in mice reflect the different forms of vitamin D examined remains to be determined.
Silent information regulator 1 (SIRT-1), a nicotinamide adenine dinucleotide-dependent deacetylase, was found to regulate cell apoptosis, inflammation, and oxidative stress response in living organisms. Therefore, the role of SIRT-1 in regulating forkhead box O/poly ADP-ribose polymerase-1 (FOXO-1/PARP-1) signaling could provide the necessary validation for developing new pharmacological targets for the promotion or inhibition of SIRT-1 activity toward radiation sensitivity. In the present study, the SIRT-1 signaling pathway is being investigated to study the possible modulatory effect of resveratrol (RSV, SIRT-1 activator) versus nicotinamide (NAM, SIRT-1 inhibitor) in case of liver damage induced by whole-body gamma irradiation. Rats were exposed to 6 Gy gamma radiation after being pretreated with either RSV (10 mg/kg/day) or NAM (100 mg/kg/day) for 5 days, and subsequent examining hepatic morphological changes and apoptotic markers were assessed. The expression of SIRT-1, FOXO-1, and cleaved PARP-1 in the liver was analyzed. RSV improved radiation-induced apoptosis, mitochondrial dysfunction, and inflammation signified by low expression of caspase-3, lactate dehydrogenase, complex-I activity, myeloperoxidase, and total nitric oxide content. RSV increased the expression of SIRT-1, whereas cleaved PARP-1 and FOXO-1 were suppressed. These protective effects were suppressed by inhibition of SIRT-1 activity using NAM. These findings suggest that RSV can attenuate radiation-induced hepatic injury by reducing apoptosis and inflammation via SIRT-1 activity modulation.
Sirtuin 1 (SIRT1) is an NAD⁺ dependent deacetylase that modify the gene expression through histone deacetylation. SIRT1 plays a crucial role in regulating a wide range of physiological processes by adjustment multiple mechanisms through the deacetylation of multiple substrates. Neurodegenerative diseases are a series of chronic diseases characterized by dysfunction and loss of neurons. Its basic pathogenesis is filamentous tangles and amyloid deposits, such as Amyloid-β (Aβ), tau protein, α-synuclein, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This summarizes introduces the structure and function of SIRT1, and then analyzes the protective effects of SIRT1 on neurological diseases by regulating circadian rhythm, aging, oxidative stress, mitochondrial dysfunction and neuroinflammation related pathways.
Quercetin and lycopene are strong dietary antioxidants that often co-exist in foods. Here, the cardiac and neuroprotective effects of quercetin and lycopene combination were analyzed in d-galactose-induced oxidative stress in mice. ICR mice were divided into control group, d-galactose group (D-GAL), quercetin treatment (Q45: 45 mg·kg⁻¹·d⁻¹quercetin, Q60: 60 mg·kg⁻¹·d⁻¹ quercetin), lycopene treatment (15 mg·kg⁻¹·d⁻¹ lycopene), and M groups (45 mg·kg⁻¹·d⁻¹quercetin+15 mg·kg⁻¹·d⁻¹ lycopene). Mice were given quercetin, lycopene, and their combination through oral gavage for 6 weeks. They were injected with d-galactose (150 mg·kg⁻¹·d⁻¹) simultaneously except for the control group. Results showed that the quercetin-lycopene combination could ameliorate histopathological injuries in the heart and hippocampus. They significantly decreased the serum and heart malonaldehyde (MDA) levels, heart 4-Hydroxynonenal (4-HNE) levels, and increased the activity of serum and heart superoxide dismutase (SOD), catalase (CAT), and the hippocampal SOD and CAT mRNA level. Quercetin-lycopene combination exhibited anti-inflammation effects by reducing inflammatory genes such as cyclooxygenase-2 (COX-2) and interleukin-1β (IL-1β). The heart and hippocampal mRNA level of nuclear factor erythroid 2-related factor 2 (Nrf2) expression was up-regulated, and the antioxidant genes related to Nrf2 including heme oxygenase-1 (HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1) were elevated. Quercetin-lycopene combination significantly promoted the mRNA level of deacetylase sirtuin-1 (SIRT1), increased 3.3-fold and 3-fold SIRT1 expression in the heart and hippocampus, respectively. They could bind SIRT1 at the active site predicted by molecular docking. These results suggested that they may interact with SIRT1 to activate Nrf2, inhibit pro-inflammatory factors, and prevent oxidative stress in D-GAL-induced mice.
Context: Low ovarian putrescine levels and decreased peak values following luteinising hormone peaks are related to poor oocyte quantity and quality in ageing women. Aims: To investigate the effects of putrescine supplementation in in vitro maturation (IVM) medium on oocyte quality and epigenetic modification. Methods: Germinal vesicle oocytes retrieved from the ovaries of 8-week-old and 9-month-old mice were divided into four groups (the young, young+difluoromethylornithine (DFMO), ageing and ageing+putrescine groups) and cultured in IVM medium with or without 1mM putrescine or DFMO for 16h. The first polar body extrusion (PBE), cleavage and embryonic development were evaluated. Spindles, chromosomes, mitochondria and reactive oxygen species (ROS) were measured. The expression levels of SIRT1, H3K9ac, H3K9me2, H3K9me3, and 5mC levels were evaluated. Sirt1 and imprinted genes were detected. Results: The PBE was higher in the ageing+putrescine group than in the ageing group. Putrescine increased the total and inner cell mass cell numbers of blastocysts in ageing oocytes. Putrescine decreased aberrant spindles and chromosome aneuploidy, increased the mitochondrial membrane potential and decreased ROS levels. Putrescine increased SIRT1 expression and attenuated the upregulation of H3K9ac levels in ageing oocytes. Putrescine did not affect 5mC, H3K9me2 or H3K9me3 levels or imprinted gene expression. Conclusions: Putrescine supplementation during IVM improved the maturation and quality of ageing oocytes and promoted embryonic development by decreasing ROS generation, maintaining mitochondrial and spindle function and correcting aberrant epigenetic modification. Implications: Putrescine shows application potential for human-assisted reproduction, especially for IVM of oocytes from ageing women.
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Interspecific competition between herbivores is widely recognized as an important determinant of community structure. Although researchers have identified a number of factors capable of altering competitive interactions, few studies have addressed the influence of neighboring plant species. If adaptation to/ epigenetic effects of an herbivore’s natal host plant alter its performance on other host plants, then interspecific herbivore interactions may play out differently in heterogeneous and homogenous plant communities. We tested wether the natal host plant of a whitefly population affected interactions between the Middle-east Asia Minor 1 (MEAM1) and Mediterranean (MED) cryptic species of the whitefly Bemisia tabaci by rearing the offspring of a cabbage-derived MEAM1 population and a poinsettia-derived MED population together on three different host plants: cotton, poinsettia, and cabbage. We found that MED dominated on poinsettia and that MEAM1 dominated on cabbage, results consistent with previous research. MED also dominated when reared with MEAM1 on cotton, however, a result at odds with multiple otherwise-similar studies that reared both species on the same natal plant. Our work provides evidence that natal plants affect competitive interactions on another plant species, and highlights the potential importance of neighboring plant species on herbivore community composition in agricultral systems.
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Oxidized low-density lipoprotein- (Ox-LDL-) induced autophagy dysfunction in human vascular endothelial cells contributes to the development of atherosclerosis (AS). Resveratrol (RSV) protects against Ox-LDL-induced endothelium injury. The objective of this study was to determine the mechanisms underlying Ox-LDL-induced autophagy dysfunction and RSV-mediated protection in human umbilical vein endothelial cells (HUVECs). The results showed that Ox-LDL suppressed the expression of sirtuin 1 (SIRT1) and increased LC3-II and sequestosome 1 (p62) protein levels without altering p62 mRNA levels in HUVECs. Pretreatment with bafilomycin A1 (BafA1) to inhibit lysosomal degradation abrogated the Ox-LDL-induced increase in LC3-II protein level. Ox-LDL increased colocalization of GFP and RFP puncta in mRFP-GFP-tandem fluorescent LC3- (tf-LC3-) transfected cells. Moreover, Ox-LDL decreased the expression of mature cathepsin D and attenuated cathepsin D activity. Pretreatment with RSV increased the expression of SIRT1 and LC3-II and increased p62 protein degradation. RSV induced RFP-LC3 aggregation more than GFP-LC3 aggregation. RSV restored lysosomal function and promoted Ox-LDL degradation in HUVECs. All the protective effects of RSV were blocked after SIRT1 was knocked down. These findings demonstrated that RSV upregulated the expression of SIRT1, restored lysosomal function, enhanced Ox-LDL-induced impaired autophagic flux, and promoted Ox-LDL degradation through the autophagy-lysosome degradation pathway in HUVECs.
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We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD(+) intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)-mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age-associated impairment in EDD was restored in OC by the superoxide (O2-) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s(-1) vs. 337 ± 3 cm s(-1) ) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2- production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen-I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO-mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s(-1) ) and EM (3694 ± 315 kPa), normalized O2- production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen-I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD(+) threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age-related arterial dysfunction by decreasing oxidative stress.
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Objectives. To ascertain if mitochondrial dysfunction (MD) of kidney cells is present in severe hemorrhagic shock and to investigate whether polydatin (PD) can attenuate MD and its protective mechanisms. Research Design and Methods. Renal tubular epithelial cells (RTECs) from rat kidneys experiencing HS and a cell line (HK-2) under hypoxia/reoxygenation (H/R) treatment were used. Morphology and function of mitochondria in isolated RTECs or cultured HK-2 cells were evaluated, accompanied by mitochondrial apoptosis pathway-related proteins. Result. Severe MD was found in rat kidneys, especially in RTECs, as evidenced by swollen mitochondria and poorly defined cristae, decreased mitochondrial membrane potential ( Δ Ψ m ), and reduced ATP content. PD treatment attenuated MD partially and inhibited expression of proapoptotic proteins. PD treatment increased SIRT1 activity and decreased acetylated-p53 levels. Beneficial effect of PD was abolished partially when the SIRT1 inhibitor Ex527 was added. Similar phenomena were shown in the H/R cell model; when pifithrin-α (p53 inhibitor) was added to the PD/Ex527 group, considerable therapeutic effects were regained compared with the PD group apart from increased SIRT1 activity. Conclusions. MD is present in severe HS, and PD can attenuate MD of RTECs via the SIRT1-p53 pathway. PD might be a promising therapeutic drug for acute renal injury.
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The endothelium is exposed to various flow patterns such as the vasoprotective unidirectional laminar shear stress (LSS), and the atherogenic oscillatory shear stress (OSS). A software-controlled, valve-operated OsciFlow device of parallel chamber was used to apply LSS and OSS to endothelial cells. While LSS inhibited superoxide overtime, OSS time dependently increased superoxide production from endothelial cells. Immunocytochemical staining revealed that at resting state, p47phox colocalizes with NOX2, while NOXO1 colocalizes with NOX1. RNAi of p47phox had no effects on superoxide or NO production in response to OSS, but significantly reduced NO production in LSS, implicating a p47phox bound NOX in mediating basal NO production. Indeed, RNAi of p47phox inhibited eNOSs1179 phosphorylation, while PEG-catalase scavenging of intracellular hydrogen peroxide or RNAi of NOX2 produced similar results, indicating a role of NOX2/p47phox-derived hydrogen peroxide at modest levels in mediating basal activity of NO production from eNOS. By contrary, RNAi of NOXO1 resulted in no significant changes in NO and superoxide levels in response to LSS, but significantly reduced superoxide while increasing NO in response to OSS. Further, we identified for the first time that OSS uncouples eNOS, which was corrected by RNAi of NOXO1. In summary, LSS activates NOX2/p47phox complex to activate eNOS phosphorylation and NO production. OSS instead activates the NOX1/NOXO1 complex to uncouple eNOS. These results demonstrate differential roles of NOXs in modulating redox state in response to different shear stress, which may promote development of novel therapeutics to mimic the protective effects of LSS while inhibiting the injurious effects of OSS.
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Inflammation and reactive oxygen species (ROS) play important roles in the pathogenesis of atherosclerosis. Resveratrol has been shown to possess anti-inflammatory and antioxidative stress activities, but the underlying mechanisms are not fully understood. In the present study, we investigated the molecular basis associated with the protective effects of resveratrol on tumor necrosis factor-alpha (TNF-α)-induced injury in human umbilical endothelial cells (HUVECs) using a variety of approaches including a cell viability assay, reverse transcription and quantitative polymerase chain reaction, western blot, and immunofluorescence staining. We showed that TNF-α induced CD40 expression and ROS production in cultured HUVECs, which were attenuated by resveratrol treatment. Also, resveratrol increased the expression of sirtuin 1 (SIRT1); and repression of SIRT1 by small-interfering RNA (siRNA) and the SIRT1 inhibitor Ex527 reduced the inhibitory effects of resveratrol on CD40 expression and ROS generation. In addition, resveratrol downregulated the levels of p65 and phospho-p38 MAPK, but this inhibitory effect was attenuated by the suppression of SIRT1 activity. Moreover, the p38 MAPK inhibitor SD203580 and the nuclear factor (NF)-κB inhibitor pyrrolidine dithiocarbamate (PDTC) achieved similar repressive effects as resveratrol on TNF-α-induced ROS generation and CD40 expression. Thus, our study provides a mechanistic link between resveratrol and the activation of SIRT1, the latter of which is involved in resveratrol-mediated repression of the p38 MAPK/NF-κB pathway and ROS production in TNF-α-treated HUVECs.
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Hypochlorite-modified albumin (HOCl-alb) has been linked to endothelial dysfunction, which plays an important role in the development of hypertension, diabetes, and chronic kidney disease. However, whether HOCl-alb induces endothelial dysfunction via vascular inflammation and whether a signaling pathway is involved are unknown and have not been investigated. HOCl-alb was found to upregulate ICAM-1 expression in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent manner. HOCl-alb time-dependently phosphorylated ERK1/2 and p 38 M A P K . HOCl-alb also activated NF- κ B. ICAM-1 expression was dose-dependently inhibited by U0126 (a specific inhibitor of MEK1/2, a signal upstream from ERK1/2), SB203580 (a specific inhibitor of p 38 M A P K ), and SN50 (a specific inhibitor of NF- κ B). U0126 and SB203580 both counteracted the activation of NF- κ B, whereas the phosphorylation of ERK1/2 and p 38 M A P K was not blocked by SN50. ERK1/2 phosphorylation was blocked by U0126 but not by SB203580, and p 38 M A P K activity was reduced by SB203580 but not by U0126. Apocynin, a specific NADPH oxidase (NOX) inhibitor, inhibited ICAM-1 expression and the activity of ERK1/2, p 38 M A P K , and NF- κ B. These results indicate that HOCl-alb-induced ICAM-1 expression is caused by the activation of a redox-sensitive intracellular signal cascade involving ERK1/2 and p 38 M A P K , culminating in the activation of NF- κ B and involving NOXs among the upstream signals.
Cadmium (Cd) is an environmental contaminant that poses serious risks to aquatic organisms and their associated ecosystem. The mechanisms underlying Cd-induced oxidative stress and immunotoxicity in fish remain largely unknown. In this study, adult female zebrafish were exposed to 0 (control), 1 mg L⁻¹ Cd for 24 h and 96 h, and the oxidative stress and inflammatory responses induced by Cd were evaluated in the brain, liver and ovary. Reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) increased in a time-dependent manner after treatment with Cd in the brain and liver. The increase may result from the disturbance of genes including copper and zinc superoxide dismutase (Cu/Zn-SOD), catalase (CAT), inducible nitric oxide synthase (iNOS), and ciclooxigenase-2 (COX-2) at mRNA, protein and activity levels. Although ROS, NO and MDA were not significantly affected by Cd in the ovary, the up-regulation of Cu/Zn-SOD, CAT, iNOS, and COX-2 was observed. Exposure to Cd induced a sharp increase in the protein levels of tumor necrosis factor alpha (TNF-α) in the brain, liver and ovary, possibly contributing to activate inflammatory responses. Furthermore, we also found a dramatic increase in mRNA levels of NF-E2-related factor 2 (Nrf2) and nuclear transcription factor κB (NF-κB) at 24 h in the liver and ovary. The corresponding changes in the mRNA levels of Kelch-like-ECH-associated protein 1 (Keap1a and Keap1b) and the inhibitor of κBα (IκBαa and IκBαb) may contribute to regulate the transcriptional activity of Nrf2 and NF-κB, respectively. Contrarily, mRNA levels of Nrf2, NF-κB, Keap1, Keap1b, IκBαa and IκBαb remained stable at 24 and 96 h in the brain. Taken together, we demonstrated Cd-induced oxidative stress and immunotoxicity in fish, possibly through transcriptional regulation of Nrf2 and NF-κB and gene modifications at transcriptional, translational, post-translational levels, which would greatly extend our understanding on the Cd toxicity.
Delayed clearance of free form all-trans-retinal (atRAL) is estimated be the key cause of retinal pigment epithelium (RPE) cells injury during the pathogenesis of retinopathies such as age-related macular degeneration (AMD), however, the underlying molecular mechanisms are far from clear. In this study, we investigated the cytotoxicity effect and underlying molecular mechanism of atRAL on human retinal pigment epithelium ARPE-19 cells. The results indicated that atRAL could cause cell dysfunction by inducing oxidative and nitrosative stressse in ARPE-19 cells. The oxidative stress induced by atRAL was mediated through up-regulation of reactive oxygen species (ROS) generation, activating mitochondrial-dependent and MAPKs signaling pathways, and finally resulting in apoptosis of ARPE-19 cells. The NADPH oxidase inhibitor apocynin could partly attenuated ROS generation, indicating that NADPH oxidase activity was involved in atRAL-induced oxidative stress in ARPE-19 cells. The nitrosative stress induced by atRAL was mainly reflected in increasing nitric oxide (NO) production, enhancing iNOS, ICAM-1 and VCAM-1 expressions, and promoting monocyte adhesion. Furthermore, above effects could be dramatically blocked by using a nuclear factor kappa B (NF-κB) inhibitor SN50, indicated that atRAL-induced oxidative and nitrosative stresses were mediated by NF-κB. The results provide better understanding of atRAL-induced toxicity in human RPE cells.