Non-coding RNA Research 8 (2023) 326–334

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Non-coding RNA Research

journal homepage: www.keaipublishing.com/en/journals/non-coding-rna-research

Review Article

An updated review on cell signaling pathways regulated by candidate

miRNAs in coronary artery disease
Imdad Khan a, Muhammad Siraj b, *
a
Department of Biotechnology, University of Malakand, Pakistan
b
Institute of Biotechnology and Genetic Engineering, University of Agriculture Peshawar, Pakistan

A R T I C L E I N F O A B S T R A C T

Keywords: MicroRNAs (miRNAs) are small endogenous non-coding RNA, size range from 17 to 25 nucleotides that regulate
Coronary artery disease gene expression at the post-transcriptional level. More than 2000 different types of miRNAs have been identified
Atherosclerosis in humans which regulate about 60% of gene expression, since the discovery of the first miRNA in 1993.
miRNA
MicroRNA performs many functions such as being involved in the regulation of various biological pathways for
Cell signalling pathway
example cell migration, cell proliferation, cell differentiation, disease progression, and initiation. miRNAs also
play an important role in the development of atherosclerosis lesions, cardiac fibroblast, cardiac hypertrophy,
cancer, and neurological disorders. Abnormal activation of many cell signaling pathways has been observed in
the development of coronary artery disease. Abnormal expression of these candidate miRNA genes leads to up or
downregulation of specific genes, these specific genes play an important role in the regulation of cell signaling
pathways involved in coronary artery disease. Many studies have found that miRNAs play a key role in the
regulation of crucial signaling pathways that are involved in the pathophysiology of coronary artery disease. This
review is designed to investigate the role of cell signaling pathways regulated by candidate miRNAs in Coronary
artery disease.

1. Introduction attained the epidemic proportion in the majority of industrialized

Coronary artery disease is also known as ischemic heart disease or
coronary heart disease [1] which involves the formation of plaque in the
arteries of the heart resulting in blood and oxygen flow reduction to the
heart muscles which may lead to myocardial infarction (MI) [2]. Coro­
nary artery disease begins with the development of plaque which may
rupture to cause myocardial infarction or stroke, inflammatory oxida­
tive stress, diminution of nitric oxide formation, foam cell formation,
and the progressive injury of endothelial cells [3]. The types of Coronary
artery disease are stable angina, unstable angina, myocardial infarction,
and sudden cardiac death [4] (see Table 1).
The burden of coronary artery disease is a great concern for
healthcare workers and patients every year about 17.9 million people
died due to coronary artery disease [5]. Death from coronary artery
disease, myocardial infarction, and stroke due to Atherosclerosis has
countries especially more common in middle-aged and older people
accounting for about 50% of all death [6]. The knowledge about the risk
factors of CAD is obtained from developed countries, but about 80% of
the global CAD burden occurs in low-income countries [7]. South Asians
at a young age are among the population, which has the highest
vulnerability to CAD development [8].
The pathogenesis of CAD as shown in Fig. 1 involves endothelial cell
dysfunctioning also referred as endothelial cell injury due to the risk
factors associated with atherogenesis. Endothelial cells released various
types of cytokines and chemokines in response to injury. Dysfunctioning
in endothelium also causes changes in the permeability, adhesion, and
growth-associated characteristics of endothelial cells. Circulating
monocytes and T-lymphocytes are attracted to the site of injury through
chemoattractant cytokines known as chemokines such as VCAM-1. Due
to the release of certain substances at the site of injury, some changes

Abbreviations: CAD, Coronary Artery Disease; miRNA, MicroRNA; MAPK, Mitogen-activated protein kinas; TNF-α, Tumour necrosis factor alpha; PIK3R2,
Phosphoinisotol-3 kinase regulatory sub unit 2; VCAM-1, Porcine vascular cell adhesion molecule; TGF-β1, Transforming growth factor-beta 1; NF-Kb, Nuclear- factor
kappa beta; PKB/PTEN, Protein kinase B; PD CD4, Programmed cell death protein 4; NLRP3, Nod-like receptor protein 3; TLR, Toll like receptor; Apaf1, Apoptotic
Protease Activating Factor 1; TRAF6, Tumour necrosis factor receptor (TNFR)-associated factor 6; JNK, JunN-terminalKinase.
* Corresponding author.
E-mail address: sirajuom2@gmail.com (M. Siraj).

https://doi.org/10.1016/j.ncrna.2023.03.007
Received 19 January 2023; Received in revised form 16 March 2023; Accepted 29 March 2023
Available online 29 March 2023
2468-0540/© 2023 The Authors. Published by KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
I. Khan and M. Siraj Non-coding RNA Research 8 (2023) 326–334

Table 1 oxidase and superoxide generation because oxygen radicals activate

Represent the reference sequence, location, targeted mRNA, and cell signaling matrix metalloproteinase [11]. The oxidative stress by BDNF induced
pathways regulated by candidate miRNA in CAD. the instability of atherosclerotic plaque hence the expression level of
Serial MicroRNA Targeted Condition in Cell signaling Ref BDNF was high in the coronary artery of patients who has unstable
No messenger CAD patients pathway angina pectoris(UAP). Abnormal protein metabolism is another risk
RNA regulated factor for the development of CAD in genetically susceptible people,
1 miRNA- SPRED1 upregulated MAPK [34] especially in those societies in which methionine consumption is high as
126 and PIK3R it contributes to endothelial cell damage in the main areas of the
2 miRNA- IRAK1 and upregulated NF-kβ [43]
vascular system [12]. C-reactive protein(CRP) which were initially used
146a TRAF6
3 miRNA-22 NLRP3 downregulated Inflammasome [49] as a clinical biomarker for the diagnosis of infection because its pro­
4 miRNA-21 PTEN upregulated AKT/PTEN [60] duction by hepatocytes increases during the acute phase of infection
5 29b PTEN upregulated JNK and NF-kβ [67] CRP has the main role in the precipitation of C- polysaccharide of
6 miRNA- IRAK1 and downregulated TLR [70] pneumococcal cell wall but recent research showed that CRP is another
146a/b TRAF6
7 miRNA- TNFa downregulated Apaf1/caspase- [87]
risk factor for the development CAD because the production of CRP is
19b dependent cell closely related to the enzyme NAD(P)H oxidase(enzyme has a role in the
signaling production of reactive oxygen species ROS) as well CRP also directly
pathway enhance the production of NAD(P)H p22phox, as a result, the produc­
8 miRNA- IRAK1 and downregulated MAPk and NF- [95]
tion of ROS increased in smooth muscles of coronary arteries. Any ab­
3614 TRAF6 kβ
normality in the production and defence mechanisms of ROS will cause
oxidative stress which is leading to produce subsequent pathological
conditions. Blood vessels produce ROS during pathological conditions
while ROS produce during mitochondrial electron transport (MET) is
encountered by antioxidant mechanisms of the body but when there is
ischemia or hypoxia MET is imbalanced which is leading to cause ATP
depletion, acidosis, mitochondrial depolarization, and cell death. ROS
works as a signaling molecule to cause endothelial cell dysfunction.
Endothelial cells play an important role in the regulation of homeostasis
and immune-inflammatory reactions and are also involved in the pro­
duction of vasodilators such as nitric oxide (NO) and vasoconstrictive
such as thromboxane (TXA2). Besides vasodilators NO also has antith­
rombotic, antiplatelet, and anti-inflammatory properties. An imbalance
in the production of vasodilating and vasoconstricting substances due to
EC dysfunctioning will lead to the development of CAD. it has been
observed that the smooth muscles of coronary arteries and macrophages
present in smooth muscles have a high level of CRP and mRNA in the
specimen obtained from CAD patients [13].
Other risk factors that have a role in coronary artery disease include
Fig. 1. Due to endothelium injury endothelial cells release proinflammatory
diabetes mellitus. Diabetes mellitus type 2 patients have two-threefold
cytokines and the permeability of endothelium is also increased as a result
monocytes, T-lymphocytes, LDL, and other substances moved inside the arterial high chances of coronary artery diseases than the normal population
wall. The LDL is oxidized upon exposure to nitric oxide, macrophages, and some [14]. Hypertension is also an important factor in the development of
enzymes such as lipoxygenase. Monocytes present in the intima differentiated CAD which may be caused due to serum cholesterols, triglyceride,
into macrophages which begin to take oxidized LDL present in the intima. adiposity, sugar level, alcohol intake, and heart rate [15]. Familial hy­
Macrophages retain the lipids which they have taken up and as the density of percholesterolemia (FH) is a dominant common autosomal abnormality
lipids increases these macrophages are referred as foam cells which will die due and the risk of premature coronary artery disease is ten to twenty times
to apoptosis but the lipids will accumulate in the intima resulting in the higher than in the normal population [16]. Like other risk factors,
blockage of coronary arteries. different types of miRNA also have a role in the pathophysiology of
coronary artery disease.
also occur in the shape of endothelial cells as a result the gap between
endothelial cells is increased, increasing the permeability to fluids, 2. MicroRNA biogenesis and its functions
lipids, leukocytes, monocytes, and lipoprotein particles especially low
density-lipoproteins (LDL) (see Fig. 2). MicroRNAs are the class of non-coding small RNA, size range from 17
The LDL moves inside to arterial wall and undergoes oxidation upon to 25 nucleotides that regulate gene expression at the post-
exposure to nitric oxide, macrophages, and some enzymes such as lip­ transcriptional level [17]. More than 2000 different types of miRNAs
oxygenase. Monocytes migrated to the intima and differentiated into have been identified in humans which regulate the expression of about
macrophages which begins to take oxidized LDL already present in the 60% of genes since the discovery of the first miRNA in 1993 [18,19].
intima. Macrophages retain the lipids which they have taken up and as MicroRNA gene is transcribed by RNA polymerase 2 formed stem-like
the density of lipids increases these macrophages are referred as foam structure called pri-miRNA (primary transcripts) about 100–120 nucle­
cells which will die due to apoptosis but the lipids will accumulate in the otides long, DGCR8 and Drosha cut some region of pri-miRNA at a
intima resulting in the blockage of coronary arteries [9]. specific location, as a result, pre-miRNA will produce about 70 nucleo­
Many factors have a role in the pathogenesis of coronary artery tides long, for further processing pre-miRNA is transported to the
disease (CAD) such as the neurotrophin (NT) family including brain- cytoplasm through exportin 5 proteins, in the cytoplasm, the dicer will
derived neurotrophic(BDNF) and nerve growth factor NT-3 which cut pre-miRNA at two opposite direction and remove the hairpin-like
plays an essential role in the growth, maintenance, survival, and death structure as a result miRNA:miRNA* duplex is formed having 2 over­
of central and peripheral neurons [10]. NTS and their receptors are also hang nucleotides at 3′ end and monophosphate at both 5’ends. The
expressed in atherosclerosis lesions because it has been observed that in miRNA:miRNA duplex is then incorporated into an RNA-inducing
cultured smooth muscle cells, BDNF enhances the activity of NAD(P)H silencing complex(RISC) which is consists of multiple proteins such as

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I. Khan and M. Siraj
Argonate. The Argonoate protein has two domains one is the PIWI
domain having Rnase H activity involved in the breaking of
single-stranded RNA and the PAZ domain which is necessary for the
binding and attachment of single-stranded RNA, the RISC complex has
the two-strands passenger and guided strand. The guided strand along
with the RISC complex will finally become complementary with the
3’untranslated region (3′ UTR) of the target mRNA as a result the mRNA
degradation will take place using the PIWI domain of Argonaute protein
[17].
MicroRNA performed and regulates many biological and physio­
logical activities such as cell migration, cell proliferation, and cell dif­
ferentiation [20]. miRNAs are also having an important role in the
development of different types of diseases such as atherosclerosis le­
sions, cardiac fibroblast, cardiac hypertrophy, cancer, and neurological
disorders [21]. Abnormal expression of different types of miRNAs has
been observed in cardiovascular diseases such as myocardial infarction,
atherosclerosis, cardiac senescence, and heart failure [22]. miRNAs are
having a key role in the development of CAD because these miRNAs
regulate the expression of cytokines which are the main actors in in­
flammatory and immunological mechanisms. In CAD proinflammatory
cytokines are expressed at a high level which has a significant role in the
formation of atherosclerotic plaque as shown in Fig. 1. Cytokines are
mainly involved in the regulation of cell signaling pathways for example
MPAK, SMAD, and STAT [23]. Besides the above, some miRNAs have a
role in lipid metabolism, as well as platelet-related miRNAs, can be used
as prognostic, diagnostic, and treatment response biomarkers in CAD
and acute coronary syndrome (ACS) [24].
3. Cell signaling pathways regulated by candidate miRNAs in
coronary artery disease
Eukaryote evolves many strategies to respond to a wide range of
environmental stresses. The response mechanism involves sensing spe­
cific stimuli, and activating the cell signaling pathway as result physi­
ological changes occur that enable the cell to tolerate and recover from
environmental stresses. Physiological changes usually involve repres­
sion or induction of particular gene expression [25]. Cell signaling
pathways regulate many cellular activities such as transport signals from
or onto the cell surface as well as inside intracellular compartments,
response to stresses, apoptosis, and protecting itself from harm
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Non-coding RNA Research 8 (2023) 326–334
(environmental agents or infection) [26]. Cell signaling, differentiation,
proliferation, and survival pathways play important roles in the regu­
lation of many cellular activities such as cell apoptosis [27]. Any ab­
normality in the regulation of these cell signaling pathways leads to
many diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s
disease(PD), Alzheimer’s disease(AD), various types of cancers, and the
development (progression) of cardiovascular diseases [28]. Many reg­
ulators regulate Cell signaling pathways such as microtubules, actin
filaments, syndecans, Lysosome, Integrin, conductance regulators, and
reactive oxygen species [29,30]. miRNAs are also having a key role in
the regulation of cell signaling pathways and abnormal expression of
many miRNAs has been observed in cell signaling pathways involved in
cell proliferation, differentiation, apoptosis, tumorigenesis, angiogen­
esis, and the process of atherosclerosis [31].
3.1. miRNA-126 role in atherosclerosis progression through MAPK cell
signaling pathway
It has been reported that miRNA-126 was involved in the regulation
of genes involved in response to different types of inflammations, pro­
moting angiogenesis, and controlling inflammation in vascular diseases
[32]. MAPK (mitogen-activated protein kinas) cell signaling pathway
played important role in the signal transduction and regulation of gene
expressions involved in inflammation leading to atherosclerosis [33].
Overexpression of miRNA-126 has a beneficial effect as it reduces the
expression level of pro-inflammatory cytokines such as IL-6 and TNF-a,
which reduces the accumulation of macrophages in atherosclerotic
lesion [34]. Through the luciferase assay, it has been reported that the
potential target of miRNA-126 is MAP3K10. MAP3K10 expression is
regulated by miRNA-126 at mRNA or proteins level in THP-1 macro­
phage and apoE− /− mice through miRNA-126 mimics or inhibitors
[34]. MAP3K10 is associated with a multi-lineage of kinase enzymes
which are involved in the phosphorylation of many proteins essential for
inflammatory and immune responses, and function in the JNK cell
signaling pathway [35]. MAP3K10 is also involved in endocytic func­
tions [36], therefore, MAP3K10 play important role in the atheroscle­
rosis process. Many studies have confirmed the anti-inflammatory role
of miRNA-126 by increasing cell proliferation of endothelial progenitor
cells, regulating the expression of VCAM-1, and promoting angiogenesis
[33]. miRNA-126 involved in the ECs response regulation induced
Fig. 2. Biogenesis of miRNA involved the transcrip­
tion of miRNA gene by RNA polymerase 2 referred as
pri-miRNA, Drosha processes pri-miRNA inside the
nucleus as a result pre-miRNA is formed which is
transported to cytoplasm through Exportin 5 for Dicer
processing. The miRNA:miRNA duplex is then incor­
porated into an RNA-inducing silencing complex
(RISC) which consists on multiple proteins such as
Argonate having two domains PIWI and PAZ as well
as consists on two strands passenger and guided
strands. The guided strand along with the RISC
complex will bind with the 3’untranslated region
(3′ UTR) of the target mRNA as a result the mRNA
degradation will take place using the PIWI domain of
Argonaute protein leading to the silencing of that
specific gene.
I. Khan and M. Siraj
through vascular endothelial growth factor (VEGF), repressing negative
regulators of VEGFA pathway such as SPRED1(sprout-related EVH1
domain-containing protein 1 and PIK3R32 (phosphoinositol-3 kinase
regulatory subunit 2) [37] as shown in figure-3 miRNA-126 is important
for the maintenance of vascular integrity. Antago miRNA-126 decreased
the ischemia–induced angiogenesis in hind limb ischemia due to an in­
crease in PIK3R2 and SPRED1 expression [38]. A recent study has found
that miRNA-126 is down-regulated in CAD patients [39].
3.2. miRNA-146a regulates cell apoptosis of vascular smooth muscle cells
in coronary
3.2.1. Heart disease via NF-kB cell signaling pathway
The nuclear factor-kappa B(NF-kB) cell signaling pathway has an
essential role in cell proliferation, growth, and signal transduction [40].
Previous studies have reported that coronary heart disease is developed
due to abnormal growth or proliferation of vascular smooth muscle cells
and activation of the nuclear factor-kappa B(NF-kB) cell signaling
pathway [41]. In different types of cells, miRNA-146a regulates cellular
growth and proliferation [42]. Results obtained from different experi­
ments reported that miRNA-146a is overexpressed in the vascular
smooth muscle of CAD patients as compared to the normal these results
indicated that miRNA-146a plays an essential role in vascular remod­
eling [43]. The vascular muscles of CAD patients have high apoptosis
and low cell proliferation and growth rate as compared to the healthy
control due to overexpression of miRNA-146a [44]. The apoptosis pro­
cess of vascular smooth muscle cells occurred through a
mitochondrial-mediated internal cell signaling pathway, not the death
receptor-mediated external cell signaling pathway [43]. NF-kB cell
signaling pathway is abnormally activated in vascular smooth muscles
of CAD patients as shown in figure-4, therefore these cells show
abnormal cellular growth and proliferation in addition to this
miRNA-146a inhibits the NF-kB cell signaling pathway as result the
apoptosis process of these cells increased apoptosis process reduced
when the inhibitors of NF-kB cell signalling pathway were used which
suggesting that miRNA-146a mediated apoptosis process in CAD pa­
tients via NF-kB cell signalling pathway [45].
3.3. miRNA-22 protects endothelial cell injury, targeting NLRP3 through
suppression of the inflammasome cell signaling pathway in coronary artery
disease
Endothelial cell injury and inflammation have an important role in
the development of atherosclerosis [46]. It has been reported that
miRNA-22 is downregulated in coronary artery disease and other dis­
eases involve an inflammatory response. Moreover, the severity of CAD
and atherosclerosis increased when NLR family pyrin
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Non-coding RNA Research 8 (2023) 326–334
domain-containing protein 3 combine with down stream cytokines,
including caspase-1 [47]. Besides the above mechanisms activation of
the NLRP3 (Nod-like receptor protein 3) signaling pathway cause
endothelial cell injury which may also lead to atherosclerosis [48]. In
inflammatory response, miRNA-22 was less expressed and also
contributed to the development of coronary artery disease [47].
Inflammasome intracellular cascade activation was initiated by NLRP3
[49]. miRNAs are the important regulators of NLRP3 Inflammasome
activity because they work as inhibitors therefore NLRP3 gene is the
potential target of miRNA-22, confirmed through dual luciferase assay
[49,50]. The endothelial cell dysfunction leads to vascular remodeling
and the development of atherosclerosis, induced through the activation
of caspases-1 [51]. NLRP3 Inflammasome production may also reduce
by miRNA-20, including a reduction in caspases-1 and NLRP3 expres­
sion [52]. The main characteristics of senescent injured endothelial cells
are an increase in inflammatory proteins, a reduction in cell prolifera­
tion rate and promoting apoptosis [53]. In CAD disease, miRNA-22
increased cellular activities and decreased apoptosis rate and these
cells still has the capability to form lumen. It has been demonstrated that
the up-regulation of miRNA-22 can prevent endothelial cell injury while
mediating apoptosis rate lumen-forming abilities and cell survival rate
[54].
3.4. miRNA-21 protects against cardiac ischemia/reperfusion injury
through AKT/PTEN cell signaling pathway via ischemia post-conditioning
Currently, the treatment option for myocardial ischemia (CAD) is
rapid reperfusion, which can reduce the effect of myocardial infarction,
reduce the apoptosis of cardiomyocytes and restore contractile dys­
functioning although reperfusion reduces mayo cordial necrosis and
mortality, many studies reported that reperfusion can itself induce both
lethal and transient injuries following ischemia, i.e. ischemia/reperfu­
sion injury [55]. Ischemic preconditioning (IPC), is a powerful endog­
enous protective mechanism that can normalize vascular endothelial
cell function, reduce apoptosis rate and size of infrared, and prevent
abnormal heartbeat due to reperfusion [56,57]. Several studies reported
that the expression of miRNA-21 can be mediated through ischemia
post-conditioning which plays an essential role in the protection against
ischemia/reperfusion cardiac injury via targeting PTEN/PKB (Protein
kinase B) cell signaling pathway [58]. PTEN is an important molecule
that plays an essential role in the development and progression of
different cardiovascular diseases because PTEN is highly expressed in
vascular smooth muscles, cardiac muscles, endothelial cells, and fibro­
blast cells. In these cells, PTEN regulates the process of contractility, cell
apoptosis/survival, hypertrophy, and metabolism through interaction
with the target molecules such as AKT and phosphoinositide-3kinases
(PI3Ks) [59]. The target gene for miRNA-21 is PTEN and this is the
Fig. 3. When a specific ligand such as VEGF binds
with its receptor(VEGFR) it will activate MAPK cell
signaling pathway which will lead to the expression
of pro-inflammatory cytokines genes (cause of
atherosclerosis). The miRNA-126 inhibits the expres­
sion of SPRED and PIK3R which are the inhibitors of
MAPK and P13k cell signaling molecules. These
molecules prevent the MAPK cell signaling pathway
from activation. If miRNA-126 is upregulated, it will
lead to the downregulation of SPRED and P13K
molecules as a result MAPK/ERK cell signaling
pathway will over-activate which will lead to the
overexpression of pro-inflammatory cytokines.
I. Khan and M. Siraj
main mechanism of miRNA-21in cardiovascular as shown in figure-5,
and the PTEN activity is lowered after Ischemia post-conditioning(IPpst)
[60]. Many studies indicated that the up-regulation of miRNA-21 due to
ischemia post-conditioning inhibits the expression of PTEN during
ischemia/reperfusion cardiac injury more ever it has been observed that
the knockdown of endogenous miRNA-21 with anatomic-21 increased
sensitivity to I/R trigged cell death. Using antagomir-21 to knock down
miRNA-21 during I/R injury also up-regulated PTEN expression [61].
Many studies demonstrated that miRNA-21 had an important role in
protection against I/R myocardial injury. The overexpression of
miRNA-21 due to ischemia post-conditioning can reduce I/R induced
apoptosis of cardiomyocytes through the AKT/PTEN cell signaling
pathway thus these studies indicated that ischemia post-conditioning
mediated miRNA-21 expression may be a promising intervention in
the management of ischemic heart diseases (CAD) [58]. A recent study
have confirmed that miRNA-21 is over express in diabetic patients result
in over expression of pro-inflammatory cytokines by activating NF-kB
cell signaling pathway which is also a risk factor for CAD development
[62].
3.5. miRNA-29b enhances lipopolysaccharides-induced endothelial cell
inflammatory damage through regulation of JNK and NF-kβ
Inflammation is a physiological response to injury or infection
Fig. 5. when a specific ligand such as TGF-B binds with its receptor e.g. TGFR it
will activate the phosphorylation process of cell signaling transducing molecule
such as Smad 2/4 as a result transcription factor NF-KB will activate which will
lead to the expression of pro-inflammatory cytokines genes. miRNA-21 targets
the mRNA of smad 7 inhibitor which prevents the activation of cell signaling
pathway, as a result, no expression of pro-inflammatory cytokine will take place
hence up-regulation of miRNA-21 will lead to down-regulate smad 7 expression
resulted in over-activation of cell signaling pathway thus increases the pro­
duction of pro-inflammatory cytokines.
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Non-coding RNA Research 8 (2023) 326–334
Fig. 4. When a specific cytokine ligand binds with its
receptor e.g. TLR it will activate adaptors molecules
(IRKA1 and TRAF6) as a result the phosphorylation of
cell signaling transducing molecules such as IKBa will
take place which will activate transcriptional factors
e.g. NF-k β inducing the expression of genes involved
in anti-apoptosis process.miRNA-146a targets the
mRNAs of IRAk1 and TRAF6 lead to the inhibition of
NF-kB cell signaling pathway as a result anti-
apoptosis gene will not express thus increases the
apoptosis process of heart muscles, as miRNA-146a is
overexpressed in CAD patients.
through acquired and innate immune systems [63]. TNF-α (Tumour
necrosis factor alpha) has an essential role in the development and
progression of vascular abnormalities via regulating the expression of
molecules involved in vascular inflammation, tone, and remodeling,
thus causing endothelial dysfunctioning [64]. Interferon-gamma(INFγ)
and interleukin-1β(IL-1β) are important factors in the regulation of in­
flammatory response [64]. It has been demonstrated that miRNA-29b is
associated with many biological processes and has a role in the devel­
opment and progression of many diseases [65]. Many studies reported
that lipopolysaccharides(LPS) promote the expression of miRNA-29b,
miRNA-29b up or down-regulation play important role in cell
apoptosis, cell viability, and release of inflammatory-related factors
such as TNFα, IL-1β, INFγ thus affect cell inflammatory damage [66].
miRNA-29b affects the expression level of TNFα, IL-1β, INFγ, down­
regulation of miRNA-29b, reduced inflammatory damage induced by
LPS in human umbilical vascular endothelial cells (HUVECs) while
overexpression of miRNA-29b enhanced LPS induced inflammatory
damage [67]. JNK (Jun N-terminal Kinase) and NF-kβ (nuclear-factor
kappa beta) are important cell signaling pathways in the regulation of
various biological processes, activated NF- kβ and JNK signaling path­
ways have a key role in an inflammatory response that could promote
the release of proinflammatory cytokines [68]. Studies demonstrated
that overexpression of miRNA-29b promoted endothelial cell inflam­
matory damage through JNK and NF-kβ cell signaling pathways in
LPS-stimulated HUVECs, from this evidence it can be concluded that
miRNA-29b may be the target for the treatment of endothelial inflam­
matory damage [67]. Recently it has been discovered that miRNA-29b
reduces myocardial ischemia reperfusion injury in rats through
reducing the expression level of PTEN and increasing the expression
level of proteins involved in Akt and eNOS cell signaling pathways [69].
3.6. miRNA-146a/b expression regulates TLR4 cell signaling pathway in
coronary artery disease
The immune response in (CAD) is initiated (regulated) by the Toll-
like receptor cell signaling pathway (TLR4). miRNA-146a/b regulate
the expression of molecules associated with the transduction of signals
such as IRAK1(interleukin-1-receptor-associated kinase 1) and TRAF6
(tumor-necrosis-factor associated factor 6) [70] as shown in figure-6.
Circulating monocytes obtain from coronary artery disease patients
contain a high level of pro-inflammatory cytokines due to the activation
of the TLR signal [71]. It has been demonstrated that atherosclerosis is
an inflammatory disease and the immune response plays an essential
role in its initiation and progression [72]. TLR4 is an important factor in
the initiation and progression of atherosclerosis [73]. Besides the above
factors infiltrating macrophages within the coronary artery which also
has a role in plaque destabilization and rupture in CAD, loss of TLR4
I. Khan and M. Siraj
Fig. 6. When a specific ligand such as IL-8 binds with its receptor e.g. TLR it
will activate adaptors molecules (IRKA1 and TRAF6) as a result the phos­
phorylation of cell signaling transducing molecules such as IKBa will take place
which will activate transcriptional factors e.g. NF-k β inducing the expression of
genes involved in the inflammation process. miRNA-146a targets the mRNAs of
IRAk1 and TRAF6 leading to the inhibition of the TLR cell signaling pathway.
when miRNA-146 is downregulated pro long activation of the TLR cell signaling
pathway will take place which will lead to the overexpression of pro-
inflammatory cytokines genes.
minimized the severity of atherosclerosis and altered atherosclerotic
plaque [74,75]. Many studies have confirmed that miRNA-146a/b reg­
ulates the TLR4 cell signaling pathway by targeting cell
signal-transducing molecules such as IRAK1 and TRAF6. The gene
responsible for miRNA-146a and miRNA-146b is located on chromo­
some 5 and 10 respectively [76]. Promotor analysis of miRNA-146a/b
reported that IRAK1 and TRAF6 are the targeted genes for
post-transcriptional gene expression control [76]. IRAK1 and TRAF6 are
involved in the activation of transcriptional factors such as NF-kβ and
AP-1(activating protein 1) which initiate the transcriptional process of
the genes involved in TLR4-mediated immune response and hence
up-regulate immune response [77]. It has been demonstrated the
expression of miRNA-146a/b is induced through pro-inflammatory
stimuli such as IL-1, TNF α, and TLR4 [78]. The expression level of
IRAK1 and TRAF6 were high in the CA group as compared to the normal
group, kinases involved in the TLR4 cell signaling pathway including
TRAF6 and IRAK1 are also activated in the CAD group [79]. The
expression level of mRNA responsible for coding of IRAK1 and TRAF6
are downregulated by miRNA-146a/b, due to which pro-longed acti­
vation of TLR4 cell signaling pathway takes place, therefor any abnor­
mality in the expression level of miRNA-146a/b may contribute to the
development of CAD [80]. A recent meta-analysis study shows that
miRNA-146a carrying the G allele may reduce the risk of CAD [81].
3.7. miRNA-19b inhibits endothelial cell apoptosis through Apaf1/
caspase-dependent cell signaling pathway in coronary artery disease
The development of the atherosclerosis process is triggered by many
pro-inflammatory factors because these factors can have destroyed the
integrity of the endothelium. (TNF-α) causes endothelial cell injury to
result in endothelial cell dysfunction [82]. The apoptosis process
involved different types of caspases such as initiator caspases including
caspase-8,-9and -10, as well as effector caspases e.g.caspase-3 and -7
[83]. TNF-α concentration increased due to risk factors associated with
(CAD) such as age, smoking, and over dieting as result caspases are
expressed at a higher level. Therefore, a decrease in the expression level
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Non-coding RNA Research 8 (2023) 326–334
of caspases helps to reduce the chances of atherosclerosis development
and its progression [83]. The apoptotic effect of TNF-α is initiated when
TNF- α bind with the receptor called TNF-α receptor type 1, which has a
role in caspases activation and recruitment [84]. The effector caspases
such as caspase-3 and -7 activated by initiator caspases e.g. 8, -9and
− 10. The apoptosome which is composed of dATP, procaspase-9, and
apoptotic protease-activating factor 1(Apaf-1) has an essential role in
the apoptosis process. Apaf1 has three primary protein domains, a
nucleotide-binding oligomerization domain, a caspases recruitment
domain, and several WD40 repeats. When cytochrome c binds to Apaf1,
the complex recruits and activates caspase-9. Apoptosome has an
essential role in the activation of downstream effector caspases, trig­
gering cell apoptosis [85]. miRNA-19b targets the mRNA responsible for
the coding of TNF-α as shown in figure-7, so the downregulation of
miRNA-19b leads to upregulation of Casp3, casp7, Apaf1, and PTEN,
resulting in the over-activation of Apaf1/caspases cell signaling
pathway which causes an increase in endothelial cell apoptosis [86].
Many studies reported that miRNA-19b is downregulated in CAD pa­
tients as compared to the normal individual as a result expression level
of TNF-α increased, which leads to enhanced apoptosis of vascular
endothelial cells [87]. Recently it has been shown that miRNA-19b is
also associated with lipid metabolism [88].
3.8. miRNA-3614 target TRAF6 molecule involved in the regulation of
inflammatory responses through MAPks and NF-kβ cell signaling pathways
in the epicardial adipose tissue with coronary artery disease
The inflammation of epicardial adipose tissue (EAT) is also an
important factor in the development of coronary artery disease. In these
conditions, the thickness of epicardial adipose tissue increases as a result
increase in macrophage infiltration and enhances immune responses
[89]. miRNAs work as regulators of the NF-kβ cell signaling pathway as
some miRNAs bind with specific inhibitors of NF-kβ cell signaling
pathway and masks phosphorylation, repress its degradation as a result
of NF-kβ cell signaling pathway activated [90]. The MAPK cell signaling
pathway has an important role in the regulation of many physiological
events such as cell cycle regulation, proliferation, and apoptosis. MAPK
Fig. 7. Apoptosis process involved two pathways: death receptor-mediated
(extrinsic) and mitochondria-dependent (intrinsic). Death receptor-mediated
pathway activated through the binding of specific ligands such as Fas and
tumor necrosis factor-(TNF)-related apoptosis-inducing ligand (TRAIL) is bind
with death receptor e.g. DR5 which recruits procaspases 8, activated caspase 8,
as a result, procaspase 3 is activated which again activate caspase 3, the main
protein involved in promoting apoptosis features such as DNA fragmentation
and cell death. miRNA-19b inhibits the expression of TNFa which leads to the
inhibition of cell apoptosis.
I. Khan and M. Siraj
pathway is involved in the phosphorylation of key enzymes, growth, and
nuclear factors, MAPK is the family of serine/threonine protein kinases
involved in several intracellular functions including cell movement,
proliferation, and apoptosis [90,91]. Studies demonstrated that in cor­
onary artery disease, the level of toll-like receptor 4(TLR4) and MI
macrophages are upregulated in endothelial adipose tissue (EAT),
showing that EAT is at low-grade inflammation [92]. TNF
receptor-associated factor 6 (TRAF6) plays an essential role in TLR
signaling, activation of nuclear factor kappa-beta (NF-kβ), and
mitogen-activated protein kinase(MAPK) cell signaling pathway [93].
TRAF6 is an important factor in the development of cardiovascular
inflammation thus regulation of TRAF6 expression is essential for the
appropriate response of the immune system [94]. miRNA-3614 directly
represses the expression of TRAF6 as shown in figure-8, through binding
with the 3′ UTR region of mRNA responsible for coding of TRAF6 hence
miRNA-3614 decreased macrophages-mediated inflammatory response
in EAT. The expression level of miRNA-3614 was lowered in endothelial
adipose tissue (EAT) of CAD patients as compared to the non-CAD group
[89]. A recent study have also confirmed that miRNA-3614 is
down-regulated in CAD patients endothelial adipose tissues(EAT) [95].
4. Conclusion
Cell signaling pathways play an important role in many cellular ac­
tivities such as cell proliferation, differentiation, survival, apoptosis, the
sensing of specific stimuli, and physiological changes e.g. repression or
induction of particular gene expression. Any abnormality in the regu­
lation of cell signaling pathways leads to many diseases such as Par­
kinson’s disease(PD), Alzheimer’s disease(AD), various types of cancers,
and the development (progression) of cardiovascular diseases. Many
factors regulate cell signaling pathways such as microtubules, actin fil­
aments, syndecans, Lysosome, Integrin, conductance regulators, and
reactive oxygen species. miRNAs are also having a key role in the
regulation of cell signaling pathways and abnormal expression of many
miRNAs has been observed in cell signaling pathways involved in cell
proliferation, differentiation, apoptosis, tumorigenesis, angiogenesis,
and the process of atherosclerosis. miRNAs have an essential role in the
pathogenesis of coronary artery disease via regulating the expression of
genes at the post-transcriptional level which has a key role in cell
signaling pathways. These miRNAs regulate the cell signaling pathways
by regulating the expression of molecules that are involved in the pro­
cess of cell signaling for example miRNA-19b regulates the expression of
TNFa which is work as a ligand in cell signaling while miRNA-3414
regulates the expression of TRAF6 and IRAK1 which are work as a
signal transducing molecule in the cell signaling process. The procedure
used to explore the role of miRNAs in CAD via regulating cell signaling
pathways involved several steps. The first step is to identify the target of
specific miRNA through various types of computer programs such as
DIANA-microT, microInspecter, miRanda, and targateScan for the
confirmation dual luciferase assay is used. The second step is to isolate
and measure the expression level of miRNAs and the target genes using
different types of techniques such as in situ hybridization, northern
blotting, microarray analysis, and real-time PCR however the most
sensitive and accurate technique is quantitative reverse transcription
PCR(qRT-PCR), and also searching the role of the targeted molecule in
the of regulation cell signaling pathways. After the quantification of
miRNA and target gene expression in CAD patients and healthy in­
dividuals the conclusion is made about specific miRNA whether it is up
or downregulated in CAD patients which is leading to up or down-
regulation of target molecule due to which dysregulation of specific
cell signaling pathway takes place. In the future, miRNA can be used as a
diagnostic and prognostic tool to identify the individual at high risk of
CAD development or monitor disease progression. Further advancement
in miRNA research could lead to the development of novel therapeutic
targets such as the development of miRNA-based therapies that will
target the specific pathway involved in the development and progression
332
Non-coding RNA Research 8 (2023) 326–334
Fig. 8. when specific ligands such as TNFα and IL6 bind with TLR receptor on
the cell surface it will activate IRAK/TRAF6 a target of miRNA-3614.These
signal-transducing molecules activate transcriptional factors e.g. NF-kβ, in­
duces expression of genes producing IL-6 and TNF-α, ultimately leading to CAD
development, thus downregulation of miRNA-3614 will result in upregulation
of TRAF6 therefore over expression of inflammatory genes will take place.
of the disease. miRNA could also be used as a prime target for the
development of personalized medicines that will target the unique
miRNA profile of the individual however certain questions need to be
addressed while using miRNA as a therapeutic target for example one
miRNA can regulate the expression of multiple genes and the expression
of a single gene can be regulated by multiple miRNAs, in this case, the
miRNA therapy for single miRNA will be not so much effective and
miRNA therapy for a specific miRNA will disrupt the functions of other
normal genes because a single miRNA can regulate the expression of
multiple genes therefore further research is needed to use miRNA as a
diagnostic and therapeutic tool for the treatment and earlier diagnosis of
CAD.
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