Drug Discovery Today  Volume 25, Number 4  April 2020 PERSPECTIVE

feature
The signaling interplay of GSK-3b in
myocardial disorders
Arun K. Sharma1, arunpharma2013@gmail.com, akumar10@ggn.amity.edu,
Punniyakoti V. Thanikachalam2 and Saurabh Bhatia1,3

Glycogen synthase kinase-3 (GSK-3) regulates numerous signaling transductions and pathological states,
from cell growth, inflammation, apoptosis, and heart failure to cancer. Recent studies have validated the
feasibility of targeting GSK-3b for its therapeutic potential to maintain myocardial homeostasis. Herein,
we review the multifactorial roles of GSK-3b in cardiac abnormalities, focusing primarily on recent

Features  PERSPECTIVE
investigations into myocardial survival. In addition, we discuss the cardioprotective potential of
divergent GSK-3b inhibitors. Finally, we also highlight crosstalk between the various mechanisms
underlying abnormal myocardial functions in which GSK-3b is involved.

Introduction
Glycogen synthase-3 (GSK-3) is a rate-limiting
serine and threonine protein kinase with two
paralogous genes, encoding GSK-3a and GSK-
3b, characterized by individual spliced variants
and kinase domains at their N and C-terminal
sequences. Additionally, GSK-3b2 is a minor
splice variant of GSK-3b (as a 13-residue insert in
the kinase domain). GSK-3b2 is commonly lo-
calized in neuronal cells, whereas the other
isoforms (GSK-3a and GSK-3b) are expressed in
numerous tissues [1]. GSK-3b regulates a range
of cellular processes by modulating various
signaling cascades, including cell proliferation,
apoptosis, and inflammation [1,2]. GSK-3 is
constitutively active in resting cells, whereas
active or upregulated GSK-3b (i.e., overexpres-
sion of GSK-3b mRNA or dephosphorylation of
GSK-3b) have been reported to induce myo-
cardial injury through increased expression of
Bax/Bcl-2 and caspase-3 in cardiomyocytes [3,4].
Conversely, phosphorylation of GSK-3 residues
can modulate its substrate-binding potential [1].
Phosphorylation of GSK-3b and a at tyrosine
216 and 279, respectively, increase the enzy-
matic activity of GSK-3. By contrast, phosphor-
ylation of GSK-3b and a at serine 9 and 21,
respectively, inactivates GSK-3 by blocking its
active site [1]. This switches GSK-3 between a
phosphorylated and dephosphorylated state,
making this a highly dynamic event that can
impact various molecular pathways.
Myocardial diseases are prevalent worldwide
and can be triggered by several risk factors,
including diabetes, obesity, mitochondrial re-
active oxygen species production, chronic
pressure overload (cardiac remodeling), release
of inflammatory cytokines, and ischemia–re-
perfusion (I/R) injury [5].
Furthermore, I/R injury leads to apoptosis,
necrosis, and oxidative stress, further adding to
cellular and tissue damage. Numerous recent
investigations have reported the cardioprotec-
tive potential of divergent GSK-3b inhibitors,
including SB216763, copper nanoparticles (NPs),
adropin, rhein, resveratrol, sevoflurane, salvia-
nolic acid, and remifentanil, against hypoxia-
reperfusion-induced myocardial insult (Table 1)
[5–12]. Moreover, myocardial hypertrophy, car-
diac fibrosis, cardiomyopathy and parasympa-
thetic dysfunction-induced myocardial damage
was ameliorated by phosphorylation of GSK-3b
[13–15]. Consequently, there has been intense
interest in developing a novel therapeutic
strategy against cardiac diseases. Here, we
summarize GSK-3b-mediated molecular signal-
ing in myocardial pathophysiology and high-
light opportunities for new drug development.
Temporal and mechanistic transduction of
GSK-3
The molecular cascades that are predicted to
support kinase inhibition and result in thera-

1359-6446/ã 2020 Elsevier Ltd. All rights reserved.

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 PERSPECTIVE Drug Discovery Today  Volume 25, Number 4  April 2020

TABLE 1
Recent evidence suggesting myocardial protection through numerous signaling cascade triggered by GSK-3b inhibition
Sr. No. Therapeutic agents Drug Impact on cardiac phenotype Involved molecular cascades Refs
(reported as GSK-3b
inhibitor)
Synthetic
1 Remifentanil Synthetic opioid Alleviates H/R-induced injury Downregulates HDAC3- [12]
analgesic drug and reduces apoptosis mediated increase in
phosphorylation of GSK-3b
2 SB-216763 Synthetic Decreases I/R injury, autophagy, Opens mPTP; reduces TNFa, [35]
ATP-competitive apoptosis, and mitochondrial IL-1b, and MCP-1
inhibitor of GSK-3b membrane potential
3 Sulforaphane Isothiocyanate Reduces cardiomyopathy Activates Nrf2 via Akt/GSK-3b/ [14]
group of Fyn pathway
organosulfur
compounds
4 Tris (1, 3-dichloro-2- Organophosphorus Reduces cardiomyocytes Reduces Ca2+-overload and [4]
propyl) phosphate flame retardants apoptosis and autophagy; activates phosphorylation of
ameliorates H/R injury Akt/GSK-3b signaling
5 Thiadiazolidine Selective non-ATP Mitigates myocardial I/R injury, Phosphorylates GSK-3b/ [10]
derivative (TDZD-8) competitive apoptosis and endoplasmic b-catenin signaling and reduces
inhibitor of GSK-3b reticulum stress mPTP activity
Proteins
6 DKK3-overexpressing Glycoprotein Reduces cardiac hypertrophy Regulates ADAM17/ACE2 and [42]
adenovirus (Dickkopf family of and fibrosis inhibits GSK-3b/b-catenin
Wnt inhibitors) pathway
7 Fibroblast growth Human protein Alleviates H/R -induced injury Phosphorylates GSK-3b/Nrf2/ [19]
factor 19 encoded by FGF19 ARE signaling
8 Follistatin-Like 3 Human protein Improves function of Increases b-catenin nuclear [47]
encoded by FSTL3 endothelial cells translocation through inhibition
of GSK-3b
9 Adropin Peptide hormone Reduces hypoxia/reoxygenation Activates RISK pathway [7]
(H/R) injury
Metals
Features  PERSPECTIVE

10 Copper nanoparticle Metal nanoparticle Attenuates I/R-induced Increases expression of [5]

myocardial infarction inflammatory cytokines through
phosphorylation of GSK-3b
11 Lithium Metal Improves parasympathetic Sterol regulatory element [48]
responsiveness binding protein 1
Herbal
12 Fisetin Plant polyphenol Alleviates myocardial I/R injury Reduces mitochondrial [28]
(Flavonoid) and mitochondrial ROS oxidative stress via inhibition of
GSK-3b
13 Genistein Isoflavone Attenuates cardiac hypertrophy Inhibits MAPK (ERK1/2, P38, [41]
JNK1/2) and AKT/GSK-3b
signaling
14 Kaempferol Natural flavonol Reduces heart failure Reduces Nrf2/NF-kB/Akt/GSK- [45]
3b signaling pathways
15 Leonurine Pseudoalkaloid Ameliorates acute myocardial Increases phosphorylation of [30]
ischemia PI3K/AKT/GSK-3b and reduces
Bax:Bcl-2 ratio and cleaved-
caspase3
16 Lycopene Carotenoid Ameliorates myocardial I/R Increases phosphorylation of [26]
hydrocarbon injury AKT/ERK1/2 and GSK-3b/mPTP
opening; reduces expression of
cytochrome c and cleaved-
caspase-9/3
17 Myrica rubra Flavonoids Attenuates H/R-induced Phosphorylates Akt/GSK-3b [20]
cardiomyocyte injury signaling pathway
18 Pterostilbene Phytophenol Protects against acute MI Improves thiol-dependent [27]
enzymes activity and GSK-3b
phosphorylation
19 Qiliqiangxin Traditional Chinese Regulates cardiomyocytes Decreases mitochondrial [40]
medication proliferation and reduce apoptosis/ROS through PI3K/
apoptosis AKT/GSK-3b signaling pathway

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Drug Discovery Today  Volume 25, Number 4  April 2020 PERSPECTIVE

TABLE 1 (Continued )
Sr. No. Therapeutic agents Drug Impact on cardiac phenotype Involved molecular cascades Refs
(reported as GSK-3b
inhibitor)
20 Qishen granules Traditional Chinese Reduces cardiac fibrosis Upregulates protein expression [15]
medicines of p-Smad3, PI3K, p-Akt, and p-
GSK-3b pathway by TGF-b1
21 Radix Salvia miltiorrhiza Traditional Chinese Ameliorates chronic myocardial Reduces Bax/Bcl-2 pathway; [29]
and Lignum Dalbergia medicines ischemia increases phosphorylation of
odorifera Akt/GSK-3b signal pathway
22 Resveratrol Stilbenoid (natural Reduces anoxia/reoxygenation Dephosphorylates VDAC1 via [9]
phenol) injury Akt-GSK-3b pathway
23 Rhein Anthraquinone Reduces H/R injury, apoptosis, Increases phosphorylation of [18]
compound and ROS production Akt/GSK-3b/p38 pathway
24 Salvianolic acid A Herbal medicine Attenuates H/R-induced injury Increases phosphorylation of [11]
and reduce apoptosis Akt/GSK-3b protein kinase
25 Shikonin Chinese herbal Attenuates H/R -induced Activates (phosphorylates) PI3K/ [21]
medicine cardiomyocyte injury Akt pathway
26 Suxiao Jiuxin Pills Chinese traditional Improves hypoxia-induced Phosphorylates PI3K/Akt/GSK- [39]
medicine cardiomyocyte injury 3b signaling pathway
27 CAPE-pNO2 Para-nitro Protects islet b cells and AMPK/GLUT4/GSK-3b/PPARa [54]
derivative of caffeic improves insulin resistance pathway
acid phenethyl
ester
28 Plantamajoside Active ingredient of Attenuates cardiac hypertrophy Inhibits mRNA and protein [31]
Herba plantaginis expression of ANP, BNP, Myh7,
COL1/3, histone deacetylase 2,
and Akt/GSK-3b
Lipid/Glycosides
29 Dioscin Spirostanyl Reduces cardiac hypertrophy Inhibits MAPK and Akt/GSK-3b/ [43]
glycoside mTOR pathways
30 S1P and LPA Bioactive lipids Regulates cardiac differentiation Modulates canonical Wnt/ [50]
and cardiomyocyte proliferation b-catenin and ERK signaling
Miscellaneous
GSK-3b inhibitor

Features  PERSPECTIVE
31 CHIR99021 Regulates cardiomyocyte Modulates canonical Wnt/ [50]
differentiation proliferation b-catenin and ERK signaling
32 Dexmedetomidine Selective a2- Alleviates myocardial I/R injury Upregulates PI3K/Akt- [22]
adrenergic receptor dependent GSK-3b
agonist phosphorylation signaling
pathway
33 Lansoprazole Proton pump Attenuates cardiac hypertrophy Downregulates Akt/GSK-3b/ [13]
inhibitor and HF b-catenin pathway
34 Sevoflurane Anaesthetic agent Decreases myocardial I/R injury, Activates GSK-3b/b-catenin [10]
apoptosis and endoplasmic signaling and reduced mPTP
reticulum stress activity
35 Sitagliptin Dipeptidyl Attenuates myocardial Increases phosphorylation of [36]
peptidase-4 apoptosis and hypertrophy AMPK and Akt/GSK-3b/p38
inhibitor AMPK

peutic effects are regulated by various upstream
and downstream effectors in the heart (Fig. 1).
Canonical Wnt signaling initiates a multiprotein
complex that includes axin, adenomatous
polyposis coli gene product (APC), GSK-3, and
b-catenin. The upregulation of Wnt signaling
inactivates GSK-3 and b-catenin by interfering
with disheveled (Dvl) protein signaling. By
contrast, the activation of p38-MAPK also inhi-
bits GSK-3 and stabilizes b-catenin. The stabi-
lized b-catenin translocates to the nucleus,
where it triggers transcriptional events by in-
volving Tcf/Lef, which suggests a key role of this
signaling pathway in the regulation of cardiac
hypertrophy. Additionally, activation of growth
factors (insulin signaling) upregulates the PI3K/
Akt pathway by binding to receptors. The PI3K/
Akt cascade negatively regulates GSK-3, leading
to its inhibition [16]. This inhibition activates
multifactorial cellular events by upregulating
various protein kinases, including glycogen
synthase (increasing glycogen storage), D and E-
type cyclins (promoting cell cycle progression),
Myc (involved in cell cycle progression and
regulation of cardiomyocyte metabolism) and
mTORC1 (regulating protein synthesis and cell
growth). The signaling transduction of GSK-3
also depends on the activation of b-adrenergic
receptor (b-AR) and various hypertrophic sti-
muli [1,2]. The activation of b-AR in response to
stress stimuli endorses cAMP and PKA activation.
This activated cellular cascade phosphorylates
and inhibits phospholamban, which increases
the contractility of myocardial tissue through a
surge of sarcoendoplasmic reticulum calcium
transport ATPase 2 (SERCA2), whereas angio-
tensin II and a-adrenergic agonist (hypertrophic
stimuli) result in increased levels of Ca2+, which
dephosphorylate members of the nuclear factor

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 PERSPECTIVE Drug Discovery Today  Volume 25, Number 4  April 2020

Growth Hypertrophic β-adrenergic

Wnt factor stimuli receptor agonist

Dvl
Hypertrophic
IRS
+ stimulation cAMP
P P P
β-catenin Dvl PI3K GSK-3α
P P
GSK-3 GSK-3 PKA
Akt
Axin APC Axin APC Ca2+
P P
GSK-3 PLB
Calcineurin
Degradation/ β-catenin
ubiquitination D/E
TcF Myc eIF2B NFAT SERCA-2a
β-catenin cyclins

Regulate Regulate cardiomyocyte Regulate Regulate

myocardial gene proliferation, metabolism hypertrophic gene cardiac
expression and protein synthesis expression contractility

Drug Discovery Today

FIGURE 1
Features  PERSPECTIVE

Diverse signaling cascade for the temporal and mechanistic transduction of GSK-3. Abbreviations: APC, adenomatous polyposis coli gene product; Akt, protein
kinase B; Dvl, Disheveled protein; eIF2B, eukaryotic initiation factor 2b; GSK3, glycogen synthase kinase-3; IRS-1, insulin receptor substrate 1; NFAT, nuclear factor
of activated T cells; PKA, protein kinase-A; PLB, phospholamban; PI3K, phosphoinositide 3-kinase; SERCA 2a, sarco/endoplasmic reticulum Ca2+-ATPase-2.

of activated T cells (NF-AT) family (responsible
for hypertrophic gene expression) through
activation of calcineurin in myocardial cells
[1,2,16].
Role of GSK-3b in myocardial I/R injury
Recent findings have focused on in vitro (hyp-
oxia/reperfusion; H/R) and in vivo (I/R) models to
explore the role of GSK-3b in myocardial in-
farction (MI). Moreover, the modulation of var-
ious prosurvival kinases has been reported in
the reperfusion injury salvage kinase signaling
(RISK) pathway. Adropin was explored for its
antiapoptotic, anti-inflammatory, and increased
cell viability effects in a I/R-subjected H9c2
cardiomyoblast cell model. The authors con-
cluded that phosphorylation of GSK-3b results
in its protective potential, which was abolished
by the use of PI3K (LY294002) and ERK1/2
(PD98059) inhibitors. These findings showed the
regulatory roles of GSK-3b that might be trig-
gered by the RISK pathway [7]. As noted earlier,
Liu et al. reported the attenuation of H/R-in-
duced cardiomyocyte (H9c2) injury by targeting
HIF-1a/GSK-3b/mPTP against oxygen glucose
deprivation; in addition, reperfusion induced an
interaction between adenine nucleotide trans-
ferase (ANT) and cyclophilin D [17]. An anthra-
quinone compound (Rhein) has also been
reported to protect H9c2 cells in an in vitro
model of myocardial H/R injury, which was
completely abolished by LY294002 or by si-
lencing of GSK-3b through siRNA, endorsing the
involvement of GSK-3b phosphorylation trig-
gered by the PI3K/Akt pathway [18]. A recent
study also highlighted the important interlink
between GSK-3b and voltage-dependent anion
channel 1 (VDAC1). Resveratrol dephosphory-
lates VDAC1 through activation of the Akt–GSK-
3b pathway, protecting cardiomyocytes against
anoxia/reoxygenation [9]. Conversely, phos-
phorylation of VDAC2 increased its affinity for
Bax and decreased its interaction with hexoki-
nase 2, resulting in the production of reactive
oxygen species (ROS), opening of mPTP, and
release of cytochrome C. Moreover, phosphor-
ylation of GSK-3 (p-GSK-3b) inhibited cell apo-
ptosis and oxidative stress caused by H/R-
induced injury through the nuclear transloca-
tion of nuclear factor E2-related factor (Nrf2).
This cytoprotective potential of Nrf2 signaling
was mediated by overexpression of fibroblast
growth factor 19 (FGF19), which is influenced by
phosphorylation of GSK-3b [19]. Further re-
search confirmed that phosphorylation of GSK-
3b at Ser 9 (by remifentanil postconditioning)
increased cell viability and attenuated apoptosis
in H9c2 cardiomyoblasts subjected to H/R injury
[12]. The increased expression of phosphory-
lated GSK-3b by salvianolic acid confirmed its
protective role against H/R injury in cardio-
myocytes by the downregulation of mPTP
opening and the induction of antiapoptotic
(reduced Bax/Bcl-2 ratio) and antioxidative
effects [11].
In addition to specific GSK-3b inhibitors, herbal
compounds (Myrica rubra flavonoids and shiko-
nin) have also shown protective potential against
H/R-induced injury in cardiomyocytes through
the phosphorylation of the PI3K/Akt/GSK-3b
pathway. Phosphorylated GSK-3b confers cyto-
protection by attenuating ROS production and

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Drug Discovery Today  Volume 25, Number 4  April 2020 PERSPECTIVE

apoptosis [20,21]. Moreover, synthetic com-
pounds, including Tris (1, 3-dichloro-2-propyl)
phosphate (TDCPP), also mitigate against H/R
injury in H9c2 cardiomyocytes by promoting the
phosphorylation of GSK-3b and reducing Ca2+
overload [4].
Thus, phosphorylation of GSK-3b by different
upstream markers endorses its protective action
in cardiomyocytes (Fig. 2). Recent in vivo
investigations also support existing evidence
that the phosphorylation of GSK-3b (directly/
indirectly triggered by PI3K/Akt signaling) could
extensively mitigate I/R injury in animal models
by encouraging cardiac preconditioning with
treatment of sevoflurane, dexmedetomidine,
and astragaloside IV [10,22,23]. Additionally,
myocardial preconditioning endorses the acti-
vation of endothelin-1, subsequently increases
cardioprotection via regulation of the Akt/GSK-
3b signaling pathway [24], which in turn causes
the downregulated expression of caspases 3 and
9 and Bcl2 in cardiomyocytes [24,25].
Numerous phytocompounds, including lyco-
pene, plantamajoside, pterostilbene, fisetin,
leonurine, and a combination of Radix salvia
miltiorrhiza and Lignum dalbergia odorifera
extracts, showed cardioprotective potential
against I/R injury via increased phosphorylation
of the Akt/GSK-3b pathway associated with
downregulated expression of the apoptotic
cascade and mitochondrial oxidative stress
[26–31]. Moreover, synthetic compounds, such
as 4-benzyl-2-(naphthalene-1-yl)-1,2,4-thiadia-
zolidine-3,5-dione (NP12), have been shown to
be allosteric inhibitors of GSK-3b that subse-
quently reduce myocardial fibrosis and increase
coronary blood flow with improved ventricular
functions [32]. Murphy et al. reported the car-
dioprotective role of GSK-3b inhibition by
delaying opening of the mitochondrial perme-
ability transition pore, which could significantly
upregulate oxidative stress and apoptotic sig-
nalling [33]. Recent research examined 6-bromo-
indirubin-3-oxime and other analogues as GSK-
3b inhibitors and concluded that the mitigation
of infarct size beyond mPTP inhibition was the
underlying mechanism [34]. Opioid-induced
myocardial protection was evaluated by using
morphine against reperfusion-induced injury.
The cardioprotective action of opioid agonists
was abrogated by prior administration of
wortmannin, indicating the involvement of GSK-
3b phosphorylation during reperfusion [35].
Additionally, Eric et al. confirmed the abolish-
ment of the cardioprotective potency of mor-
phine during diabetes because of the upstream
regulation, or reduced phosphorylation, of
GSK-3b [36].
Thus, the results discussed herein confirm the
role of GSK-3b inhibition and/or phosphoryla-
tion in protecting cardiomyocytes against I/R-
induced injury.
Role of GSK-3b in cardiomyocyte
apoptosis
Apoptosis of myocardial cells is another leading
cause of myocardial damage [heart failure (HF),
cardiac fibrosis and cardiomyopathy] during
hyperglycemia, MI, and Ca2+ deposition. Recent
investigations revealed that diabetes mellitus
(DM) significantly reduced GSK-3b phosphory-
lation at Ser 9, initiating cardiac apoptosis.

GSK-3βkinase phosphorylates numerous upstream factors (including PI-

GSK-3β inhibitor 3K/Akt signaling, RISK pathway, and HIF-1α), which in turn promotes
factors regulating myocardial structure and function

Features  PERSPECTIVE
Plasma membrane

Cytoplasm
Overexpressed
P GSK-3β DKK-3

Phosphorylation at Ser 9

TGF-β Nrf2 p38 MAPK mTOR mPTP Dephosphorylation Ca2+ overload ADAM 17
of VDAC2
NF-κB Endothelin-1 β-catenin nuclear
Accumulation of Fyn Hexokinase-2 Profibrotic
translocation
in nucleus ANT protein
TNF-α
transforming Bax:Bcl2
Cyclophilin D ROS growth
IL-1β NrF2 Regulation of ratio
Gene Expression factor TGF
β/SMAD2/3
MCP-1 Overexpressed Cytochrome C
Apoptosis H/R injury signaling ANP/BNP
FGF19
Oxidative stress
induces cardiac injury Caspase-3/9 β-myosin
Bax:Bcl2 ratio Myocardial structural
heavy chain
and Apoptosis
Inflammatory Collagen volume
mediator
functional regulation Hypertrophic and fibrotic marker fraction

Drug Discovery Today

FIGURE 2
Schematic diagram of the GSK-3b phosphorylation-mediated amelioration of pathological events, including hypertrophy, cardiomyocyte proliferation,
apoptosis of cardiac cell, and heart failure. Abbreviations: ADAM17, ADAM metallopeptidase domain 17; ANP, atrial natriuretic peptide; ANT, adenine nucleotide
translocator; BNP, B-type natriuretic peptide; CypD, cyclophilin D; DKK-3, Dickkopf Wnt signaling pathway inhibitor 3; FGF19, fibroblast growth factor 19; H/R
injury, hypoxia/reoxygenation injury; IL-1b, interleukin-1b; MCP-1, monocyte chemoattractant protein-1; mTOR, mammalian target of rapamycin; NF-kB,
nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid-2-related factor 2; p38 MAPK, p38 mitogen-activated protein
kinases; ROS, reactive oxygen species; TGF-b, transforming growth factor beta; TNF-a, tumor necrosis factor alpha; VDAC2, voltage-dependent anion-selective
channel protein 2.

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 PERSPECTIVE
Conversely, the activation of Akt signaling fol-
lowed by GSK-3b inhibition by SB216763 re-
stored apoptosis in cardiac cells [6]. FGF19 has
an important role in cytoprotection by miti-
gating cell apoptosis and oxidative stress. At the
same time, it also regulates the phosphorylation
of GSK-3b and Nrf2 in H/R-subjected cardio-
myocytes, highlighting its antiapoptotic po-
tential [19]. Xin et al. reported the mitigation of
Ang II-induced cardiomyopathy in mice by sul-
foraphane treatment through the upregulation
of Nrf2 via GSK-3b inhibition, confirming the
involvement of Nrf2 and GSK-3b in cardiomy-
opathy [14]. Furthermore, Potz et al. revealed
that inhibition of GSK-3b reduced collagen
formation, oxidative stress, markers of profi-
brotic protein (involved in TGFb/SMAD2/3 sig-
naling, and apoptosis-inducing factors in
myocardial tissues during chronic myocardial
ischemia [25]. By contrast, it has also been found
that adrenomedullin (a potent inhibitor of ap-
optosis) can significantly increase the survival
rate of mesenchymal stem cells in response to
hypoxia-induced apoptosis through increased
expression of Akt/GSK-3b phosphorylation and
Bcl2 signaling pathways [37]. Several recent
investigations highlighted the pharmacological
application of GSK-3b inhibition against apo-
ptosis via downregulation of apoptosis-inducing
Features  PERSPECTIVE
factors [4,25,38]. DM significantly influences
caspase 3 and Bax expression while downre-
gulating Bcl2 expression, which leads to cardiac
apoptosis. Additionally, DM can also downre-
gulate Akt and AMPK phosphorylation, which
subsequently augments the dephosphorylation
of GSK-3b or activation of GSK-3b and causes
cardiac apoptosis [39]. Similarly, TDCPP also
protected cardiomyocytes against oxidative
stress-induced apoptosis and autophagy by
mitigation of dephosphorylation of the Akt/GSK-
3b signalling pathway. TDCPP also reduced the
Ca2+ overload, providing additional protection
for cardiomyocytes against apoptosis [40].
GSK-3b inhibitors (a thiadiazolidine deriva-
tive; TDZD-8) and sevoflurane preconditioning
also prevented cardiomyocyte apoptosis
through increased expression of phosphorylat-
ed GSK-3b and b-catenin [10]. Selective a2
adrenergic agonist (dexmedetomidine) post-
conditioning against I/R-induced cardiac dam-
age in diabetic rats also mitigated apoptosis via
the phosphorylated Akt/GSK-3b signaling cas-
cade [41]. Moreover, some herbal extracts
[Qiliqiangxin (QLC) capsules, Myrica rubra, and
Suxiao Jiuxin Pill] showed antiapoptotic po-
tential by regulating PI3K/Akt/GSK-3b against
H/R-induced cardiomyocyte apoptosis in H9c2
cells [20,42,43]. More interestingly QLC capsules
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Drug Discovery Today  Volume 25, Number 4  April 2020
reduced oxidative stress and mitochondria-de-
pendent Bax expression and apoptotic protease
synthase kinase-1 levels [43].
Thus, these studies suggest that GSK-3b has a
key role in the protection of cardiomyocytes
against apoptosis (Fig. 2).
Role of GSK-3b in hypertrophic
cardiomyopathy and heart failure
Hypertrophic cardiomyopathy is the most
common inherited cardiac abnormality, result-
ing in significant mortality. Cardiac remodelling
is a physiological event in response to pressure
overload, humoral factors, and I/R induced
myocardial stress. Conversely, chronic stress
endorses maladaptive remodelling and subse-
quently leads to HF [13,39]. Numerous impaired
molecular events are involved in cardiac remo-
delling, including cardiac hypertrophy and fi-
brosis [13,39]. Although cardiac stress triggers
fibroblast proliferation and secretion of proin-
flammatory cytokines, recent studies explored
the possible involvement of GSK-3b in hyper-
trophic cardiomyopathy [13,39,44,45]. Chen
et al. revealed that dioscin exerts cardiomyocyte
protection by attenuating hypertrophic events
and recovering impaired cardiac functions
against Ang II-induced cardiac hypertrophy. The
protective effect of dioscin involved the inhibi-
tion of the MAPK and Akt/GSK-3b/mTOR path-
ways [46]. Additionally, authors also observed
similar results for the action of sitagliptin against
apoptosis and hypertrophy in diabetic cardio-
myopathy. Sitagliptin endorsed the mitigation
of cardiac hypertrophy by phosphorylation of
Akt/AMPK, followed by inactivated expression of
GSK-3b and p38 MAPK as the underlying
mechanism [39]. Furthermore, the overexpres-
sion of Dickkopf WNT Signaling Pathway In-
hibitor 3 (DKK3) has been shown to attenuate
the pathology in Ang II-induced cardiac hyper-
trophy and fibrosis. The protective pathways of
overexpressed DKK3 triggered the inhibition of
ADAM17 phosphorylation, and GSK-3b/
b-catenin and b-catenin translocation to the
nucleus (Fig. 2) [45]. A recent study showed that
genistein (a tyrosine kinase inhibitor) can also
reduce the detrimental expression of hyper-
trophic and fibrotic events by suppressing their
markers, including collagen volume fraction,
atrial natriuretic peptide, brain natriuretic
peptide, b-myosin heavy chain, tissue growth
factor, and TGF. The above consequences
revealed the antihypertrophic potential of ge-
nistein via the regulation of MAPK and Akt/GSK-
3b signaling [44].
Conversely, Morishige et al. revisited the
study of cardiomyocyte hypertrophy induced by
isoprenaline and revealed alternative conse-
quences of GSK-3b in cardiac hypertrophy. The
authors suggested that the cardioprotective
potential of 2,5-dimethylcelecoxib was con-
ferred by activation of Akt and GSK-3b or in-
hibition of Akt phosphorylation resulting in
activation of GSK-3b and inhibition of the
b-catenin/mTOR signaling pathways [47]. Fur-
thermore, in line with Morishige et al. [47], Lin
et al. explored the antihypertrophic potential of
a proton pump inhibitor (lansoprazole) by
measuring the levels of myocardial phosphor-
ylated Akt/GSK-3b and active b-catenin [13].
Although the activation of GSK-3b was not clear
in terms of the inhibition of phosphorylation of
GSK-3b on Ser 9, lansoprazole associated with a
reduction in the phosphorylation of GSK-3b was
observed in transverse aortic constriction or a
sham surgery group as well as in patients with
Ang II-subjected cardiomyopathy, explaining
the overall reduction of GSK-3b phosphoryla-
tion. These results suggest that lansoprazole
provides cardioprotection by suppressing the
activation of the Akt/GSK-3b/b-catenin path-
way in Ang II-stimulated cardiomyocytes, indi-
cating the favourable regulation of the GSK-3b
pathway [13,47]. However, the underlying mo-
lecular consequences remain unclear.
Role of GSK-3b in regulation of cardiac
fibrosis and HF
The accumulation of cardiac fibrosis triggered
by activated cardiac fibroblasts is the root cause
of detrimental cardiac remodelling. There is
abundant cardiac fibroblast involvement in MI,
leading to the loss of cardiac function. Thus,
there is a need to fully understand the molecular
pathways that can significantly target such
cardiac damage. Zeng et al. reported a tradi-
tional Chinese formula (Qishen Granules) to
protect against myocardial damage and cardiac
fibrosis [15]. Pathological progress in cardiac
fibrosis and HF was reversed by this traditional
formula through inhibition of TGF-b and
phosphorylation of GSK-3b, confirming the
ameliorating role of GSK-3b signaling in HF in
Sprague–Dawley rats [15]. A specific inhibitor
(SB-216763) of GSK-3b has also been investi-
gated against aldosterone-induced cardiac in-
jury. Aldosterone infusion significantly increased
the expression of inflammatory cytokines and
fibrosis. However, treatment with SB-216763
attenuated these pathological events and re-
stored the structure and function of the myo-
cardium, indicating the activation of autophagy
in myocardial tissue, which the authors con-
cluded to be a possible mechanism of protec-
tion [38]. Moreover, overexpression of DKK3 was
Drug Discovery Today  Volume 25, Number 4  April 2020
reported to downregulate ADAM17 phosphor-
ylation, which limits its potential to cleave ACE2
expression, subsequently mediated by GSK-3b
inhibition and the b-catenin pathway (Fig. 2)
[45]. Kaempferol (natural flavanol) reduced the
symptoms of hyperglycaemia and isoprotere-
nol-induced HF in diabetic animals. Kaempferol-
associated cardioprotection was initiated by
regulation of the Akt/GSK-3b/p38 MAPK sig-
naling pathway [48]. Moreover, Lin et al. inves-
tigated the use of lansoprazole to protect
against cardiac hypertrophy and HF. The un-
derlying mechanism for this protection was
inactivation of the Akt/GSK-3b/b-catenin
pathway, which alleviated cardiac remodelling
[13]. Despite such results, the role of GSK-3b
phosphorylation in HF needs to be fully clarified,
particularly in terms of any direct linkages, and
this could lead to the development of appro-
priate therapeutic agents.
Role of GSK-3b in inflammatory cascades
Elevated inflammatory cascades have a key role
in the triggering and establishment of cardiac
complications because the innate immune sys-
tem exclusively participates in the pathogenesis
of cardiovascular diseases. Coronary heart dis-
ease is related to the pathologies of athero-
sclerosis and MI, associated with a passive
process involving lipid deposition and inflam-
mation in the subintimal space of arteries,
leading to their occlusion. A recent study
revealed that limb remote ischemic postcondi-
tioning and a7 nicotinic acetylcholine receptor
(a7nAChR) agonists exhibited cardioprotective
effects in rats through increased expression of
GSK-3b phosphorylation at Ser 9. Furthermore,
the underlying mechanism was shown to in-
volve GSK-3b phosphorylation-dependent
downregulation of nuclear factor-kB (NF-kB)
expression, supporting the attenuation of in-
flammatory events (Fig. 2) [49]. In addition,
SB216763 (a GSK-3b inhibitor) was shown to be
involved in aldosterone-induced hypertrophy
and fibrosis. The results confirmed the reduced
levels of inflammatory cytokines (TNF-a, IL-1b,
and monocyte chemotactic protein-1) by ad-
ministration of SB216763. Moreover, treatment
with SB216763 increased the level of LC3-II and
p63 degradation in cardiac tissue, leading to the
activation of autophagy in aldosterone-treated
cardiac tissue [50]. Administration of Ang II
triggered cardiac remodelling by influencing
oxidative stress and inflammatory events.
However, Xin et al. reported that sulforaphane
ameliorated the development of Ang II-induced
cardiomyopathy by upregulating and activating
Nrf2. Intriguingly, this upregulation of Nrf2 was
activated by Akt/GSK-3b phosphorylation
pathways that lead to the accumulation of Fyn in
the nucleus and trigger the activation of Nrf2.
These consequences of cardioprotection were
abolished with treatment with a PI3K inhibitor or
GSK-3b specific activator, supporting the
involvement of the PI3K/Akt/GSK-3b signal-
ing pathway [14]. In a similar context, re-
search revealed the direct involvement of
GSK-3b in diabetes and associated inflam-
mation in islets of Langerhans, where lithium
significantly decreased the expression of
proinflammatory cytokines and improved
glucose metabolism [51].
GSK-3b regulation in cardiac
development and miscellaneous risk
factors
GSK-3b regulates various prime molecular cas-
cades involved in cardiovascular functionality.
GSK-3b has a key role during the mid to later
phase of cardiomyocyte differentiation, whereas
its deletion causes cardiomyocyte proliferation
[52]. Deletion of GSK-3b, and to a lesser extent,
GSK-3a, significantly downregulated the dif-
ferentiation of human pluripotent stem cells
(hPSCs). Laco et al. observed various differenti-
ation stages of multiple hPSC lines following
GSK-3b inhibition and varying culture condi-
tions [52]. Thus, inhibition of GSK-3b appears to
be a critical brake in cardiomyocyte differenti-
ation during early phases of development,
whereas the inhibition of GSK-3b profoundly
increases cell cycle progression through cyclin
D, and modulation of Wnt signaling and tran-
scription factors during later phases of differ-
entiation [52]. Furthermore, cardiac
differentiation during early phases of develop-
ment is also modified through activation of
bioactive lipids, including sphingosine-1 (S1P)
and lysophosphatidic acid (LPA), in hPSC-de-
rived cardiomyocytes [53]. Upregulated cell
differentiation during the early developmental
stages via S1P and LPA was achieved with a GSK-
3b inhibitor (CHIR99021) and was associated
with nuclear accumulation of b-catenin and
upregulation of the canonical Wnt signaling
pathway [53]. Conversely, later phases of cardi-
omyocyte differentiation were mediated by
upregulated ERK signaling in addition to S1P
and LPA [53]. These results support the physi-
ological role of GSK-3b inhibition during both
the early and later stages of cardiac cell devel-
opment, offering an opportunity for the precise
targeting of drugs and selection of cardiac dis-
ease models. Moreover, inhibition of GSK-3b
improved the function of endothelial cells de-
rived from PSCs. Recent research revealed that
PERSPECTIVE
vagal stimulation either during the preischemic
or reperfusion stage resulted in similar cardio-
protective potential to the pre- and postcondi-
tioning of ischemia myocardium. Intriguingly, it
was found that preischemic vagal stimulation
increased Akt and GSK-3b phosphorylation,
whereas vagal stimulation during the reperfu-
sion phase triggered the a7-nicotinic acetyl-
choline receptor and JAK-2 pathways [54]. In
addition, it was revealed that specific deletion of
GSK-3b led to cardiac dysfunction in high-fat
diet-induced obesity model [55]. Given that
research suggests obesity as is a major risk factor
for the development of cardiac diseases, it
would be of value to determine the precise role
of GSK-3b inhibition in obesity and associated
cardiovascular diseases. Conversely, vascular
calcification is another individual risk factor for
cardiovascular mortality. Atherosclerosis (intimal
calcification) and increased vascular stiffness
(medial calcification) significantly abolish vas-
cular compliance, and the phosphorylation of
GSK-3a/b through PKB/serum and glucocorti-
coid-inducible kinase increase the regulation of
vascular calcification [56].
Concluding remarks
GSK-3b inhibition is an emerging tool for tar-
geting clinical intervention in cardiovascular
Features  PERSPECTIVE
diseases and is a niche area for new drug de-
velopment. We focused here mainly on recently
reported GSK-3b inhibitors and their molecular
interaction in myocardial pathology, with em-
phasis on up- and downstream signalling
transduction. Increasing lines of evidence reveal
phosphorylation of GSK-3b (Ser 9) to be an
essential negative regulator of cardiac diseases.
Moreover, the inhibition of GSK-3b is a key
mechanism contributing to cardiac disease de-
velopment [52,53].
Emerging evidence indicates the involvement of
GSK-3b in multiple biological processes, including
metabolism, cell fate determination, proliferation,
and gene expression [1,2,16,51–53,57]. Moreover,
the signaling cascade of GSK-3b predominantly
regulates post-translational modifications, cellular
trafficking, substrate priming, protein complexes,
and regulatory mechanism. Thus, GSK-3b is a
multifactorial and constitutively active kinase that
could ameliorate myriad myocardial signalling
cascades through specific phosphorylation of Ser 9
and could form the basis of novel therapeutic
strategies in the future.
Acknowledgement
The authors are grateful to the authority of the
Amity Institute of Pharmacy, Amity University,
www.drugdiscoverytoday.com 639
 PERSPECTIVE
Haryana-122413, India for providing the
necessary facilities.
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*Corresponding author.
Features  PERSPECTIVE
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