The protective effects of 17-β estradiol and SIRT1 against cardiac hypertrophy: a review

Abstract

One of the major causes of morbidity and mortality worldwide is cardiac hypertrophy (CH), which leads to heart failure. Sex differences in CH can be caused by sex hormones or their receptors. The incidence of CH increases in postmenopausal women due to the decrease in female sex hormone 17-β estradiol (E2) during menopause. E2 and its receptors inhibit CH in humans and animal models. Silent information regulator 1 (SIRT1) is a NAD+-dependent HDAC (histone deacetylase) and plays a major role in biological processes, such as inflammation, apoptosis, and oxidative stress responses. Probably SIRT1 because of these effects, is one of the main suppressors of CH and has a cardioprotective effect. On the other hand, estrogen and its agonists are highly efficient in modulating SIRT1 expression. In the present study, we review the protective effects of E2 and SIRT1 against CH.

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Heart Failure Reviews
https://doi.org/10.1007/s10741-021-10171-0
The protective effects of17‑β estradiol andSIRT1 againstcardiac
hypertrophy: areview
ZahraHajializadeh1· MohammadKhaksari2
Accepted: 7 September 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021
Abstract
One of the major causes of morbidity and mortality worldwide is cardiac hypertrophy (CH), which leads to heart failure.
Sex differences in CH can be caused by sex hormones or their receptors. The incidence of CH increases in postmenopausal
women due to the decrease in female sex hormone 17-β estradiol (E2) during menopause. E2 and its receptors inhibit CH
in humans and animal models. Silent information regulator 1 (SIRT1) is a NAD+-dependent HDAC (histone deacetylase)
and plays a major role in biological processes, such as inflammation, apoptosis, and oxidative stress responses. Probably
SIRT1 because of these effects, is one of the main suppressors of CH and has a cardioprotective effect. On the other hand,
estrogen and its agonists are highly efficient in modulating SIRT1 expression. In the present study, we review the protective
effects of E2 and SIRT1 against CH.
Keywords 17-β estradiol· SIRT1· Cardiac hypertrophy· Estrogen receptors
Introduction
One of the major causes of morbidity and mortality world-
wide is cardiovascular disease [1]. There are 17.3 million
deaths each year and it is predicted to reach more than 23.6
million by 2030 [2]. Almost all types of heart failure are
associated with cardiac hypertrophy (CH) [3]. Systolic or
diastolic wall stress increases chronic physiological process
in cardiac muscle mass characterizing CH. This usually hap-
pens in response to sustained exercise, during pregnancy,
and during development [4]. Moreover, a number of patho-
logical conditions, such as valvular disease, hypertension,
cardiomyopathy, and myocardial infarction may cause it [5].
CH at the cellular level is determined by increasing cell size,
reactivation of fetal gene program, and protein synthesis,
eventually leading to heart failure [6].
Types ofcardiac hypertrophy
Physiological hypertrophy can be determined by the nor-
mal organization of cardiac structure along with natural or
increased contractile function [7]. Physiological hypertro-
phy is triggered by pregnancy, exercise (athlete's heart), or
growth factor stimulation [8]. Physiological hypertrophy is
identified by normal or increased cardiac function, normal
survival, and absence of pathological features like apopto-
sis and fibrosis [9]. Pathological hypertrophy is determined
by increased diastolic function and decreased systolic func-
tion, which often leads to heart failure and is associated with
increased cardiomyocyte death [4]. Pathological hypertrophy
is caused by various stimuli such as obesity, hypertension,
stenosis, or heart valve failure [4]. Early events that cause
CH are humoral stimulation and mechanical stress, which
are associated with cellular responses modulation, including
protein synthesis, sarcomere assembly, gene expression, cell
metabolism [10–12]. Physiological hypertrophy differs from
pathological hypertrophy in terms of signaling pathways that
control these processes. Research studies have indicated that
left ventricular hypertrophy (LVH) leads to long-term harm-
ful effects and short-term benefits, while the mechanism that
regulates the transition from adaptive to maladaptive hyper-
trophy has not yet been determined [13].
* Mohammad Khaksari
mkhaksari@kmu.ac.ir
1 Physiology Research Center, Institute
ofNeuropharmacology, Kerman University ofMedical
Sciences, Kerman, Iran
2 Endocrinology andMetabolism Research Center, Kerman
University ofMedical Sciences, Kerman, Iran
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Depending on heart geometry, CH can be divided into
other types, including eccentric and concentric hypertrophy.
Eccentric hypertrophy is caused by volume overload and
enhanced ventricular volume with coordinated growth in-
wall, and septal thickness indicates non-pathological eccen-
tric hypertrophy. Cardiac diseases, such as dilated cardio-
myopathy and myocardial infarction may cause pathological
eccentric hypertrophy, leading to ventricular dilatation with
cardiomyocytes preferential lengthening. Pathological con-
centric hypertrophy is characterized by an increase in the
septal thickness and free wall related to a decrease in the
left ventricular dimension. The increase in cardiomyocytes
thickness is usually greater than the length, occurring under
pathological situations including valvular heart diseases or
hypertension [14, 15]. However, non-pathological concentric
hypertrophy may be caused by exercise like wrestling [8].
Cardiac dysfunction is also dependent on other patho-
physiological conversions, such as inflammation, metabolic
derangement, apoptosis, and oxidative stress [16–18]. Due
to their complexity, simple remedial methods are not suf-
ficient to manage this situation. Given that signaling path-
ways in pathological hypertrophy are created as a result of
excessive biomechanical stress or hormonal factors, there are
several overlaps between pathological CH and physiological
mechanisms.
Estrogen andits receptors (ERs)
17β-estradiol (E2) is the main female steroid hormone and
this is the main form of circulating estrogen. The other two
natural forms occurring less frequently are estrone (E1) and
estriol (E3), and the third one produced only during the preg-
nancy is estretrol (E4) [19]. In premenopausal women, the
ovaries mostly synthesize and secrete the E2. Several tissues
produce some E2, such as the brain, adipose, aortic smooth
muscle cells, vascular endothelium, and bone tissues [20].
Extragonadal generation of E2 acts locally as an intracrine
or paracrine factor in the tissue where it is synthesized, while
gonadal E2 acts mostly as an endocrine factor that affects
distal tissues [20]. Given that extragonadal E2 is still the
only source of endogenous E2 generation in postmenopausal
men and women, its generation plays a major role [20].
E2 mainly binds to classical estrogen receptors (ERs),
estrogen receptor α (ERα), and estrogen receptor β (ERβ)
[21] and non-classical estrogen receptor GPER (G protein-
coupled estrogen receptor) [22]. In general, the genomic
effect can be created by binding to ERα and ERβ [23] and
rapid non-genomic function induced by binding to GPER
[22]. It has recently been reported that in addition to intracel-
lular localization of ERα and ERβ, they are also membrane
bound. E2 binds to membrane-bound ERα, ERβ, and GPER
for rapid non-genomic function [24–26].
Silent information regulator 1 (SIRT1)
Sirtuins are a preserved family of histone deacetylase
(HDACs) whose activity can extend the lifespan of many
organisms [27]. It was established, in 1999, that the human
SIRT1 gene is placed at 10q21.3 [28], encoding a protein
of amino acids747 [29]. The catalytic core contains a great
Rossmann fold domain which is described as a small zinc
finger domain and an NAD+/NADH binding protein [30].
There are NAD binding sites and near a NAD glycosylation
site, an acetylated substrate is bound to the end of the gap.
SIRT1 structure characterizes its role in cellular activi-
ties, including DNA repair, metabolic regulation, DNA rep-
lication, and gene transcription. SIRT1 uses deacetylation of
histones and a multitude of non-histone proteins to regulate a
set of cellular activities important for metabolism, apoptosis,
cell senescence, transcriptional regulation, cell growth, and
cell survival [31]. SIRT1 is the main regulator of metabo-
lism in various tissues [32]. Moreover, other targets of non-
histone SIRT1 protein include nuclear factor kappa B (NF-
κB), forkhead transcription factor O (FOXO), tumor protein
53 (p53), and peroxisome proliferator-activated receptor-γ
coactivator-1α (PGC-1α) [33, 34].
Cardioprotective mechanisms ofestrogen
andERs
It has been revealed that inflammation, apoptosis, and oxida-
tive stress are mainly involved in the mechanism responsible
for injury of many organs, especially the cardiovascular sys-
tem (Fig.1) [35]. Estrogen has protective effects in various
organs via inhibition of inflammation, apoptosis, and oxida-
tive stress [36, 37]. On the other hand, abnormal ER signal-
ing leads to the development of a number of diseases such as
cardiovascular diseases, cancer, and obesity, mainly through
inflammation, apoptosis, and oxidative stress mechanisms
[36–39] (Table1).
Anti‑inflammatory actions ofestrogen
andERs
Studies suggested that estrogens have a protective effect
against heart disorders by influencing the inflammatory
response [40–42] (Table1). E2 increase Cystathionine-
F-lyase (CSE) expression and reduce inflammation in the
myocardium of OVX rats [36]. It has been revealed that E2
inhibits expression of the inflammatory cytokines IL-1β
(interleukin-1β) and TNF-α (tumor necrosis factor-α) in
myocytes of old OVX [43] and in the ischemic hearts of
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OVX rats [44]. Findings suggested that the activation of
ERα reduced endotoxin-induced inflammatory response
in cardiomyocyte cells [45]. In female murine hearts, ERα
confers cardioprotection after ischemia/reperfusion (I/R)
and regulates cytokine expression [46]. Estrogen reduces
TNF-α responses via ERβ activation in rat aortic smooth
muscle cells [47]. ERβ protects myocardial function fol-
lowing I/R via a reduction in IL-1β, IL-6 (interleukin-6),
and TNF-α in normal female mice hearts [48]. In addition,
G-1(a selective agonist of GPER) induced pro-survival
and anti-inflammatory effects after I/R by decreasing the
production of IL-1β, IL-6, and TNF-α [49].
Anti‑apoptotic actions ofestrogen andERs
Many growth factors, cytokines, and hormones control
apoptosis in different ways [50]. It is known that E2 reg-
ulates the balance between proliferation, cell survival,
and apoptosis via different mechanisms [51] (Table1).
E2 inhibits apoptosis-regulated signaling kinase-1 and
prevents congestive heart failure in mice [52]. Also, E2
through activation of PI3K/Akt (Phosphoinositide-3
kinase/protein kinase B) signaling leads to a reduction in
cardiomyocyte apoptosis invivo and invitro models [53].
Fig. 1 Mediatory mechanisms of estrogen and ERs in reducing
inflammation, apoptosis, and oxidative stress against cardiac dys-
function. increase; decrease; ┴ inhibit; ERα estrogen receptor α;
ERβ estrogen receptor β; GPER G protein-coupled estrogen receptor;
TNF-α tumor necrosis factor-α; IL-1β interleukin-1β; IL-6 interleu-
kin-6; CSE cystathionine-F-lyase; H2S hydrogen sulfide; CINC-2β
cytokine-induced neutrophil chemoattractant; MCP-1 monocyte che-
moattractant protein; ACAA2 acetyl coenzyme A acyltransferase 2;
ASK1 apoptosis signal-regulating kinase 1; JNK c-Jun N-terminal
kinase; p38 MAPK p38 mitogen-activated protein kinase; PI3K/Akt
phosphatidylinositol 3-kinase/protein kinase B; ROS reactive oxygen
species; GSH/GSSG glutathione/oxidized glutathione ratio; T-AOC
total antioxidant capacity; CAT catalase; SOD superoxide dismutase;
Nox4 NADPH oxidase 4; Pgts2 prostaglandin-endoperoxide synthase
2; Gpx1 glutathione peroxidase 1
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Table 1 Mechanisms related to estrogen and ERs-mediated cardioprotection
Study model Effects on heart and
mechanism involved Sex Species Year Reference
Inflammation I/R animal model E2 improves cardiac
recovery due to
reduced TNF-α level
Female Rat 2006 Xu etal. [44]
Menopausal aging model E2 leads to cardioprotec-
tive HSP response due
to inhibited expression
of IL-1β and TNF-α
Female Rat 2011 Stice etal. [43]
OVX animal model E2 has cardioprotective
effects due to increased
CSE expression and
H2S generation and
decreased IL-6 and
TNF-α levels
Female Rat 2013 Zhu etal. [36]
TNF-α-induced inflam-
matory
E2 via ERβ has cardio-
protective effects due
to reduced CINC-2β
and MCP-1 mRNA
expression
Male Rat 2007 Xing etal. [47]
I/R animal model G-1 protects cardiac
function due to dimin-
ished TNF-α, IL-1β,
and IL-6
Male Rat 2010 Weil etal. [49]
I/R animal model ERα and ERβ mediates
acute myocardial pro-
tection due to reduced
TNF-α, IL-1β, and
IL-6 in females
Female and Male Mice 2006, 2008 Wang etal. [46, 48]
In vitro cell culture NG-R1 via ERα protects
cardiomyocytes due
to decreased TNF-
α, IL-1β, and IL-6
mRNA expression
– H9c2 cell 2015 Zhong etal. [45]
Apoptosis Ischemia-induced
apoptosis
E2 protects the heart
against ischemic dam-
age due to reduced
caspase-3 activity and
prevented release of
cytochrome c
Female Rat 2006 Morkuniene etal. [55]
MI animal model E2 inhibits cardiomyo-
cytes apoptosis due to
activation of PI3K/Akt
signaling
Female Mice 2004 Patten etal. [53]
I/R injury in OVX
animal
ERβ improves car-
diac recovery due to
decreased cytochrome
c releaseand increased
levels of Bcl2 and
ACAA2
Female Mice 2016 Schubert etal. [57]
Gαq transgenic animal
model
E2 prevents conges-
tive heart failure due
to decreased ASK1,
JNK, and p38 MAPK
activity
Male Mice 2007 Satoh etal. [52]
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E2 treatment can inhibit mitochondria‐dependent and ova-
riectomy‐induced cardiac Fas‐dependent apoptotic path-
ways in OVX or menopause rat models [54]. Moreover,
E2 inhibits ischemia-induced apoptosis through reduc-
tion of caspase-3-like activity and prevents the release
of cytochrome c in female rat hearts [55]. The activation
of ERα decreased endotoxin-induced apoptosis [45] and
autophagy in cardiomyocyte cells [56]. Also, it has been
shown ERβ attenuates apoptosis and development of fibro-
sis, in pressure overload [37], and under I/R injury in OVX
mice [57]. In addition, GPER diminished cardiocyte apop-
tosis following I/R injury in myocardial cells [58].
Anti‑oxidative stress actions ofestrogen
andERs
There is a general agreement that oxidative stress leads to
cardiovascular dysfunction [59]. Estrogens have protective
effects against oxidative stress on various tissues including
the heart. E2 diminishes angiotensin II (Ang II)-induced free
radical production and stimulates the expression of super-
oxide dismutase (SOD) in vascular smooth muscle cells
[60], and in the myocardium of OVX rats [36] (Table1).
E2 reduced ROS generation in cardiomyocytes by attenuat-
ing the p38α mitogen-activated protein kinase (MAPK) and
I/R ischemia/reperfusion, HSP heat shock protein, CSE cystathionine-F-lyase, H2S hydrogen sulfide, CINC-2β cytokine-induced neutrophil che-
moattractant, MCP-1 monocyte chemoattractant protein, G-1 GPR30 agonist, NG-R1 notoginsenoside R1, ACAA2 acetylcoenzyme A acyltrans-
ferase 2, ASK1 apoptosis signal-regulating kinase 1, JNK c-Jun N-terminal kinase, p38 MAPK p38 mitogen-activated protein kinase, GSH/GSSG
glutathione/oxidized glutathione ratio, T-AOC total antioxidant capacity, CAT catalase, SOD superoxide dismutase, VSMC vascular smooth mus-
cle cells, MI myocardial infarction, ERβ−/−/TAC ERβ knockout/transverse aortic constriction, Nox4 NADPH oxidase 4, Pgts2 prostaglandin-
endoperoxide synthase 2, Gpx1 glutathione peroxidase 1
Table 1 (continued)
Study model Effects on heart and
mechanism involved Sex Species Year Reference
ERβ−/−/TAC animal
model
ERβ inhibits cardiac
hypertrophy and heart
failure due to reduced
apoptosis
Female and Male Mice 2010 Fliegner etal. [37]
In vitro cell culture NG-R1 via ERα protects
cardiomyocytes due to
decreased caspase-3
activity
– H9c2 cell 2015 Zhong etal. [45]
In vitro cell culture ERα protects car-
diomyocytes due to
diminished caspase-3
activity
– H9c2 cell 2018 Chen etal. [56]
In vitro cell culture G-1 prevents myocar-
dial ischemia due to
elevated Bcl-2 levels,
and decreased Bax
– H9c2 cell 2015 Li etal. [58]
Oxidative stress OVX animal model E2 has cardioprotective
effects due to increased
GSH/GSSG ratio,
T-AOC, CAT, and
SOD activity
Female Rat 2013 Zhu etal. [36]
Ethanol-induced myo-
cardial oxidative stress
ERα inhibits myocardial
dysfunction due to
decreased ROS genera-
tion
Female Rat 2016 Yao and Abdel-Rahman
[62]
GPER knockout model E2 has cardioprotective
effects due to reduced
GSH/GSSG ratio and
Nox4, Pgts2, and Gpx1
genes expression
Female Mice 2018 Wang etal. [63]
In vitro cell culture E2 has vasoprotective
effects due to increased
MnSOD mRNA
expression
– VSMCs cell 2003 Strehlow etal. [60]
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enhancing the p38β MAPK activity [61]. Also, it has been
reported that E2 and ERα inhibit ethanol-induced myocar-
dial oxidative stress in female rats [62]. Findings have shown
that GPER KO leads to enhancement of cardiac oxidative
stress measured as a reduced ratio of glutathione to oxidized
glutathione (GSH/GSSG) and increased oxidative stress-
related genes expression in mice [63].
Estrogen andERs effects againstCH
Several studies have shown the effect of gender in cardiovas-
cular diseases [64, 65], as it is less probable, compared to men,
that premenopausal women will suffer cardiovascular diseases
including hypertrophy [66, 67]. Sex differences during cardiac
pathological hypertrophy can be related to sex hormones or
their receptors [68]. Hypertension or other non-ischemic factors
are the most common reason for heart failure in women, espe-
cially in postmenopausal situations [69, 70]. The mechanisms
of estrogens’ cardioprotective role have been studied, and it
seems that both classical ERs are involved to some extent [71].
Endothelial cells, mostly express ERα, while ERβ stimulates
nitric oxide production. Hence, vascular wall dilation, which
has useful hypotensive effects, activates both receptors [72, 73].
It has been indicated that plasma membrane is linked to
the non-nuclear fraction of ERα which is responsible for vas-
cular functions resulting from estrogens, including endothe-
lial NO production, endothelial repair acceleration, and rapid
dilatation [74]. In addition, Ang II activation has an incre-
ment effect on myocyte hypertrophy via calcineurin induction,
expression of β-MHC, the activation of extracellular signal-
regulated kinase (ERK), and mitogen-activated protein kinases
(MAPK). Inhibition of Ang II and its signaling pathway can
cause E2-induced protection of cardiac muscle [75]. Also,
estrogen inhibits salt-induced CH development in proANP
(atrial natriuretic peptide) gene-disrupted mice [76] (Table2).
Both classical ERs participate in cardioprotective effects of
estrogen on CH [77, 78] through the following mechanisms:
blocking of the enhanced p38-MAPK phosphorylation, increas-
ing the expression of ANP, suppressing calcineurin/NF-AT3
signaling pathways, PI3K/Akt upregulation [79–81], lowered
peripheral artery resistance and reduced systolic blood pressure
[82]. Moreover, activation of GPER and G-1 administration
inhibits Aldo-induced hypertrophy and Ang II-induced hyper-
trophy in cardiac myocytes [83, 84] via the activation of the
PI3K-Akt-mTOR signaling pathway [85] (Table2).
Cardioprotective mechanisms ofSIRT1
SIRT1 expression is abundant in mammalian hearts, and
many cell functions are regulated by the deacetylation of
histones and some non-histone proteins [86]. SIRT1 as a
cardioprotective molecule is frequently found in the nucleus
and is widely considered in the cardiovascular system, tak-
ing part in intracellular signaling in the heart [87] (Table3).
Evidence represents the preventive role of SIRT1 in heart
injuries (Fig.2) [88, 89], such as dilated cardiomyopathy
in patients and post-myocardial infarction in rats [90], oxi-
dative stress, and ischemia/reperfusion (I/R) injury, hyper-
trophy, and cardiomyocyte apoptosis [91–93]. In addition,
SIRT1 is recognized as an anti-atherosclerosis factor due to
its anti-inflammatory, anti-apoptotic, and antioxidant activi-
ties in the endothelium [93–95].
SIRT1 anti‑inflammatory effects
There is a pro-inflammatory profile in the vasculature of
animals and humans specified by an increase in the num-
ber of chemokines and cytokines [96, 97]. Furthermore,
inflammation is the main mechanism of cardiovascular
disease [98]. Therefore, inflammation results in prevent-
ing the progression of cardiovascular diseases [99]. Various
studies have indicated that SIRT1 can decrease inflamma-
tion caused by heart failure, and myocardial hypertrophy
[100, 101]. Moreover, it has been confirmed that dioscin
protects against coronary heart disease (CHD) by reducing
inflammation via SIRT1/Nrf2 and p38 MAPK pathways
[102]. The PE-induced increment in CH is also prevented
by SIRT1 in mRNA levels of the pro-inflammatory cytokine
monocyte chemoattractant protein-1 (MCP-1) and also it
inhibits the increased nuclear factor-kB (NF-kB) activity
associated with PE exposure [100]. In addition, the observa-
tions have revealed SIRT1’s inhibitory role against CH in
the SIRT1–PPARα interaction [100] because invitro evi-
dence has shown that RSV in PPARα-null mice does not
inhibit isoproterenol-induced CH and inflammation [100].
It has been reported that Kallistatin (KS, a serine protease
inhibitor) by promoting the SIRT1 expression decreases
the inflammation of myocardial tissue in heart failure rats
[103].
SIRT1 anti‑apoptotic effects
Apoptosis involves complex mechanisms. Interactions
between apoptotic factors and SIRT1 may be associated
with subcellular localization. Transcription factors like
FOXO, Ku70, and p53 are firstly deacetylate by SIRT1 in
the nucleus, to suppress responses to downstream apoptosis
cell signaling and thus prevent cell death [104].
It has been revealed that heart failure, age-dependent CH,
and apoptosis can be reduced by increasing the concentra-
tion of SIRT1 in the heart [87]. SIRT1 also suppresses the
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activity of pro-apoptotic p53 and regulates the activity of
p53 via deacetylation [105], thereby decreasing cardiomyo-
cyte apoptosis [106]. Inhibition of SIRT1 causes an increase
in acetylation level and p53 activity, so leading to cardio-
myocytes’ death and heart failure [107, 108]. The results
represent that when cellular apoptosis is caused by oxida-
tive stress, SIRT1 expression increases to prevent apoptosis
and preserve myocardiocytes [109]. SIRT1 inhibited cellu-
lar injury in myocardial infarction by activating Bcl-xL and
thioredoxin-1, and repressing activities of Bax and cleaved
caspase-3 [92]. In addition, it has been demonstrated that
KS via promoting the SIRT1 expression diminished Bax
and caspase-3/9 activities [103]. It has been revealed that
RSV protects cardiomyocytes against hypoxia-induced
apoptosis via miR-30d-5p/SIRT1/NF-κB axis [110] and
SIRT1–FOXO1 pathway [93].
SIRT1 anti‑oxidative stress effects
The overproduction of reactive oxygen species (ROS)
including oxygen free radicals and related entities, such
as peroxynitrite, singlet oxygen, nitric oxide (NO), hydro-
gen peroxide (H2O2), and superoxide free radicals, leads
to oxidative stress [111]. Various studies have shown the
destructive effects of oxidative stress on vascular and car-
diac aging [112, 113]. Other findings have revealed that
oxidative stress is involved in CH and other cardiovascular
diseases [114]. SIRT1 is considered a strong intracellular
inhibitor of oxidative stress and inflammatory responses.
The probable role of SIRT1 against cardiovascular disease
has been considered due to its inhibitory effect against
oxidative stress [114]. SIRT1 and IGF-1 are the two main
regulators of cardiomyocyte cardiac stress [96, 112]. IGF-1
uses SIRT1 to protect the heart against oxidative stress
[113]. Endothelial cells pretreatment with RSV increases
SIRT1 levels and activity, leading to less nitric oxide syn-
thase acetylation [98] (Table3). Another study has shown
the protective effects of RSV on endothelial blood vessels
[115].
Overexpression of SIRT1 protected against oxidative stress
via CH, cardiac dysfunction, apoptosis/fibrosis, and induced
the expression of catalase [87]. Crosstalk between the ROS
signaling and SIRT1 stimulates the autophagy reduction
response in the mice cardiac muscle [87, 116]. It has been
established that the increment in the catalase expression is
induced via the FOXO1 transcription factor. SIRT1 inactivates
FOXO factors through the deacetylation of these factors and
also stimulates antioxidants expression (MnSOD and catalase)
and enhances SIRT1 expression via an auto-feedback loop [87,
Table 2 Protective effects of estrogen and ERs against CH
ANP atrial natriuretic peptide, BNP brain natriuretic peptide, TAC transverse aortic constriction, p38-MAPK p38 mitogen-activated protein
kinase, βMHC beta-myosin heavy chain, SHR spontaneously hypertensive rats, AAC abdominal aortic constriction, G-1 GPR30 or GPER ago-
nist, AngII angiotensin II, Ald aldosterone, NRCM neonatal cardiac ventricular myocytes, CH cardiac hypertrophy
Study model Effect on the heart and mechanism involved Sex Species Year References
SHR animal model ERβ agonist 8β-VE2 diminishes hypertrophy
due to reduced cardiac afterload
Female Rat 2008 Jazbutyte etal. [82]
AAC-induced CH E2 decreases CH due to suppressed cal-
cineurin/NF-AT3 signaling pathways and
up-regulating PI3K/Akt
Female Rat 2005 Wu etal. [80]
SHR animal model E2 or 16α-LE2 agonist attenuates CH due to
increased cardiac output, α-MHC, and ANP
expression
Female Rat 2005 Pelzer etal. [78]
SHR animal model G-1 inhibits CH due to diminished ANP and
BNP mRNA expression
Male Rat 2020 Di Mattia etal. [83]
ANP + / − animal model E2 inhibits hypertrophy due to reduced ANP
and BNP mRNA expression
Male and female Mice 2007 Sangaralingham etal. [76]
ER − / − /TAC induced model E2 via ERβ prevents CH due to prohibited
p38-MAPK phosphorylation and elevated
ANP expression
Female Mice 2006 Babiker etal. [79]
TAC-induced CH E2 and 16α-LE2 agonist suppress myocardial
hypertrophy due to decreased BNP, ANP,
and β-MHC
Female Mice 2012 Westphal etal. [81]
AngII-induced hypertrophy E2 through ERβ reduces CH due to stimu-
lated BNP and decreased α/β MHC ratio
andinhibited calcineurin activity
Female Mice 2008 Pedram etal. [75]
Ald-induced hypertrophy G-1 inhibits CH due to decreased BNP pro-
tein expression and BNP protein/DNA ratio
– NRCM cell 2020 Di Mattia etal. [83]
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Heart Failure Reviews
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117]. So, it reduces the deterioration of cardiac function and
hypertrophy, suppresses fibrosis, and improves survival [90,
117, 118].
SIRT1 controls the ROS production through NF-κB sign-
aling [119, 120] and in this way reduces the expression of
inducible nitric oxide synthase (iNOS) and increases genera-
tion of reactive nitrogen radicals [121]. Moreover, by increas-
ing endothelial nitric oxide synthase (eNOS), SIRT1 can
enhance cardiac tolerance to oxidative stress and ischemia
[122] (Table3).
SIRT1 effects againstCH
The studies indicate that SIRT1 plays an extensive role
against CH and other cardiovascular deficits. Control of
endothelial angiogenic activities during vascular growth
[123] and abnormal cardiac growth in the SIRT1-knockout
mouse model [124] demonstrate the key role of SIRT1
in heart formation [125]. Also, under stress condi-
tions (e.g., starvation), SIRT1 increased cardiomyocyte
growth because inhibition of SIRT1 function leading to
Table 3 Mechanisms related to SIRT1-mediated cardioprotection
CHD coronary heart disease, DOX doxorubicin, HF heart failure, KS kallistatin, PE phenylephrine, NCM neonatal cardiomyocyte, ISO isopro-
terenol, MCP-1 monocyte chemoattractant protein-1, Tg-SIRT1 SIRT1 transgenic mice, mIGF-1 insulin-like growth factor-1 isoform, TBARS
thiobarbituric acid reactive substances, HUVECs human umbilical vein endothelial cells, eNOS endothelial nitric oxide synthase, Mn-SOD man-
ganese superoxide dismutase, ROS reactive oxygen spices, RSV resveratrol, PO pressure overload
Study model Effect on the heart and mecha-
nism involved Sex Species Year References
Inflammation CHD model induction Dioscin via SIRT1 protects against
CHD due to reducedTNF-α,
IL-1β, IL-6, and IL-18 levels
Male Pig 2018 Yang etal. [102]
DOX-induced HF KS via SIRT1 inhibits HF due to
reducedTNF-α, IL-1β, IL-6, and
IL-18 levels
Male Rat 2020 Xie etal. [103]
ISO-induced hypertrophy SIRT1–PPARα interaction inhibits
CH due to decreased NF-kB and
MCP-1 mRNA levels
Male Rat 2011 Planavila etal. [100]
In vitro cell culture SIRT1–PPARα interaction inhibits
CH due to decreased NF-kB and
MCP-1 mRNA levels
– NCM cell 2011 Planavila etal. [100]
Apoptosis I/R animal model SIRT1 protects the heart against
I/R due to activated Bcl-xL and
thioredoxin-1 and suppressed
cleaved caspase 3 activity and Bax
through the upregulation of FOXO
Male Mice 2010 Hsu etal. [92]
Cardiac-specific Tg-SIRT1 SIRT1 prevents cardiac dysfunction
due to elevated Bcl-2 and Bcl-xL
expression
Male Mice 2007 Alcendor etal. [87]
DOX-induced HF KS via SIRT1 inhibits heart failure
due to reduced Bax and cas-
pase3/9 activity
Male Rat 2020 Xie etal. [103]
In vitro cell culture RSV protects cardiomyocytes due
to reduced cleaved caspase 3
– H9c2 cell 2020 Han etal. [110]
Oxidative stress Cardiac-specific Tg- SIRT1 SIRT1 prevents heart failure due to
increased mIGF-1 expression
Male Mice 2012 Bolasco etal. [113]
PO-induced CH RSV via SIRT1 prevents CH due to
reduced TBARS
Male Rat 2010 Wojciechowski etal. [129]
SIRT1-induced Mn-SOD RSV via SIRT1 prevents heart fail-
ure due to increased Mn-SOD
Male Hamster 2010 Tanno etal. [90]
In vitro cell culture SIRT1 inhibits endothelial dysfunc-
tion due to eNOS acetylation
– HUVECs 2010 Arunachalam etal. [98]
In vitro cell culture SIRT1 promotes vascular tone due
to eNOS deacetylation
– Endothelial cell 2007 Mattagajasingh etal. [122]
In vitro cell culture RSV via SIRT1 protects the heart
due to decreased ROS and
increased Mn-SOD
– C2C12 cells 2010 Tanno etal. [90]
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Heart Failure Reviews
1 3
cardiomyocyte death [107] (Table4). It has been demon-
strated that SIRT1 leads to resistance to CH increase in
response to both physiologic and pathologic hypertrophic
stimuli [126]. The study showed that a low to moderate
SIRT1 expression has protective effects against cardiac
dysfunction, apoptosis, and age-related CH [87]. Addi-
tionally, SIRT1 overexpression inhibits cardiac dysfunc-
tion and age-dependent CH [87, 127]. Findings show that
mIGF‐1 (insulin-like growth factor-1 isoform) protects
cardiomyocytes against CH via SIRT1 activity [91]. The
results regarding the beneficial effects of SIRT1 on CH are
caused by the following mechanism(s):
Inhibition of poly (ADP-ribose) polymerases 2 (PARP-2)
protein and mRNA levels [128] reduce the oxidative stress
by increasing the antioxidants expression (e.g., catalase)
[87, 129] (Tables3 and 4), increase the ability of fibro-
blast growth factor 21 (FGF21) [130], activate adenosine
monophosphate-activated protein kinase (AMPK) [131]
(Table4), decrease the mRNA expressions of ANP and
β-MHC (β-myosin heavy chain) [131], and activate Akt
[132, 133].
SIRT1 andestrogen crosstalk
Studies revealed that SIRT1 is necessary for modulating
ERα-signaling pathways (Fig.3). HDACs are directly asso-
ciated with ERα protein, regulating its downstream gene
transcription [134, 135]. ERα and its downstream gene tran-
scription are suppressed by inhibiting SIRT1 activity [136].
On the other hand, SIRT1 is a unified player activated by
estrogens, via ERs [137].
It has been shown that cardiovascular dysfunction in post-
menopausal metabolic syndrome (PMS) is inhibited by E2
through its effect on SIRT1/AMPK/H3 acetylation. Downregu-
lation of SIRT1/AMPK/H3 acetylation in the aorta and heart is
related to cardiac apoptosis induced by PMS. Ang II-induced
contractions and H3 acetylation are partially suppressed by
Fig. 2 Mediatory mechanisms of SIRT1 in reducing inflammation,
apoptosis, and oxidative stress against cardiac dysfunction. increase;
decrease; ┴ inhibit; SIRT1 silent information regulator 1; TNF-α
tumor necrosis factor-α; IL-1β interleukin-1β; IL-6 interleukin-6; IL-
18 interleukin-18; MCP-1 monocyte chemoattractant protein; NF-kB
nuclear factor kappa B; Bcl-xL B cell lymphoma-extra-large; TBARS
thiobarbituric acid reactive substances; eNOS endothelial nitric oxide
synthase, ROS reactive oxygen species; mIGF‐1 insulin-like growth
factor-1 isoform; MnSOD manganese superoxide dismutase
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Heart Failure Reviews
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Table 4 Protective effects of SIRT1 against CH
AAC abdominal aortic constriction, ANF atrial natriuretic factor, BNP brain natriuretic peptide, β-MHC β-myosin heavy chain, PARP-2 poly
(ADP-ribose) polymerase-2, PO pressure overload, TBARS thiobarbituric acid reactive substances, ANP atrial natriuretic peptide, AMPK adeno-
sine monophosphate-activated protein kinase, Tg-SIRT1 SIRT1 transgenic, CH cardiac hypertrophy, Ang II angiotensin II, FGF21 fibroblast
growth factor 21, PE phenylephrine, TAC transverse aortic constriction, Bcl-xL B cell lymphoma-extra-large, mIGF‐1 Insulin-like growth fac-
tor-1 isoform, ACTA-1 skeletal muscle alpha-actin gene, MDA malondialdehyde, ROS reactive oxygen species, UCP-1 uncoupling protein-1, MT-
2 melatonin receptor 2, MCP-1 monocyte chemoattractant protein-1, NF-kB nuclear factor kappa B
Study model Effect on the heart and mechanism involved Sex Species Year References
AAC-induced hypertrophy SIRT1 prevents CH due to decreased ANF, BNP, β-MHC
mRNA and PARP-2 mRNA and protein expression
Male Rat 2013 Geng etal. [128]
PO-induced CH RSV via SIRT1 prevents CH due to reduced TBARS Male Rat 2010 Wojciechowski etal. [129]
TAC- induced CH SIRT1 inhibits CH due to decreased ANP and β-MHC
mRNA expressions by AMPK activation
Male Rat 2018 Dong etal. [131]
Ang II-induced CH SIRT1 inhibits CH due to increased FGF21 Male Mice 2019 Li etal. [130]
Cardiac-specific Tg-SIRT1 SIRT1 prevents CH due to elevated Bcl-2 and Bcl-xL
expression
Male Mice 2007 Alcendor etal. [87]
In vitro cell culture SIRT1 inhibits CH due to decreased ANP and β-MHC
mRNA expressions by AMPK activation
– Myocardial cell 2018 Dong etal. [131]
In vitro cell culture SIRT1–PPARα interaction inhibits CH due to decreased
NF-kB and MCP-1 mRNA levels
– NCM cell 2011 Planavila etal. [100]
In vitro cell culture SIR2α inhibits CH due to decreased ANF mRNA expres-
sion, cleaved caspase 3 activity and p53 acetylation
– NRVMs 2004 Alcendor etal. [107]
In vitro cell culture SIRT1 via mIGF‐1 inhibits CH due to diminished ANP,
BNP, ACTA-1 mRNA, and ROS, MDA protein levels
and increased adiponectin, UCP-1, and MT-2 mRNA
expression
– HL‐1 cell 2010 Vinciguerra etal. [91]
Fig. 3 Probable interaction between estrogen and SIRT1 against car-
diac hypertrophy. Inflammation, apoptosis, and oxidative stress seem
to be among the most important mechanisms involved in the devel-
opment of myocardial hypertrophy. On the other hand, estrogen can
reduce or inhibit oxidative stress, apoptosis, and inflammation by
regulating the expression of SIRT1 protein, thereby reducing the inci-
dence of pathological CH. increase; ┴ inhibit; ERα estrogen recep-
tor α; SIRT1 silent information regulator 1, GPER G protein-coupled
estrogen receptor
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Heart Failure Reviews
1 3
E2, and they also restore the SIRT1/P-AMPK protein expres-
sion [138]. Estrogen therapy elevates the P-AMPK and SIRT1
expression, supporting the opinion that E2 could have cardio-
protective effects on PMS [139, 140]. It has been reported that
E2 inhibits brain ischemic stroke and cardiac ischemia through
SIRT1/P-AMPK signaling [141, 142].
It has been demonstrated that E2 can increase SIRT1
expression and reduce PPARγ and adipogenesis in aged
mice and in cell culture models [143, 144]. Moreover, SIRT1
is upstream of ERα and it is responsible for promoting the
expression of ERα [136]. On the other hand, ERα is upstream
of SIRT1 in breast cancer cells and binds to the SIRT1 pro-
moter to induce SIRT1 gene expression [145]. SIRT1 expres-
sion in white adipose tissue (WAT) from ERα knockout mice
was reduced, indicating that ERα may act as an upstream of
SIRT1 [146]. In line with that, SIRT1 is upstream of ERα, it
has been shown ERα protein is decreased by SIRT1 knockout
and estrogen-responsive genes are eventually reduced [136].
Findings have been revealed that E2 and the selective GPER
agonist G-1 induce SIRT1 expression in cancer cells through
the rapid activation of the EGFR signaling [147].
Conclusions
CH is an important critical component of cardiac remod-
eling. Knowledge of CH has advanced dramatically over the
past decade and various modifiers involved in hypertrophy
and important signaling molecules have been identified. The
main regulator of physiological processes is estrogen, and
its deficiency is associated with CH and other cardiovascu-
lar diseases and leads to a disease-promoting state in post-
menopausal women. Given that the increase in SIRT1 has
a protective role in cardiomyocyte injury during CH, since
there is a crosstalk between estrogen and SIRT1, it can be
said that estrogen may improve the prognosis of CH and
protect the heart from injury by modulating SIRT1 signaling
and inhibiting oxidative stress, inflammation, and apoptosis.
Therefore, it is recommended that SIRT1 be used as a new
treatment strategy alone or in combination with estrogen in
postmenopausal women with cardiac hypertrophy.
Authors’ contributions ZH and MK reviewed the literature and wrote
the paper. Both authors read and approved the final manuscript.
Funding This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declarations
Ethics approval and consent to participate This article does not contain
any studies with human participants or animals performed by any of
the authors.
Conflicts of interest The authors declare that there are no conflicts of
interest.
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