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. 2023 Mar 29;8(3):326–334. doi: 10.1016/j.ncrna.2023.03.007

An updated review on cell signaling pathways regulated by candidate miRNAs in coronary artery disease

Imdad Khan a, Muhammad Siraj b,∗
PMCID: PMC10106733  PMID: 37077752

Abstract

MicroRNAs (miRNAs) are small endogenous non-coding RNA, size range from 17 to 25 nucleotides that regulate gene expression at the post-transcriptional level. More than 2000 different types of miRNAs have been identified in humans which regulate about 60% of gene expression, since the discovery of the first miRNA in 1993. MicroRNA performs many functions such as being involved in the regulation of various biological pathways for 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.

Keywords: Coronary artery disease, Atherosclerosis, miRNA, Cell signalling pathway

1. Introduction

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]. Coronary artery disease begins with the development of plaque which may rupture to cause myocardial infarction or stroke, inflammatory oxidative 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).

Table 1.

Represent the reference sequence, location, targeted mRNA, and cell signaling pathways regulated by candidate miRNA in CAD.

Serial No MicroRNA Targeted messenger RNA Condition in CAD patients Cell signaling pathway regulated Ref
1 miRNA-126 SPRED1 and PIK3R upregulated MAPK [34]
2 miRNA-146a IRAK1 and TRAF6 upregulated NF-kβ [43]
3 miRNA-22 NLRP3 downregulated Inflammasome [49]
4 miRNA-21 PTEN upregulated AKT/PTEN [60]
5 29b PTEN upregulated JNK and NF-kβ [67]
6 miRNA-146a/b IRAK1 and TRAF6 downregulated TLR [70]
7 miRNA-19b TNFa downregulated Apaf1/caspase-dependent cell signaling pathway [87]
8 miRNA-3614 IRAK1 and TRAF6 downregulated MAPk and NF-kβ [95]
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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 attained the epidemic proportion in the majority of industrialized 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 also occur in the shape of endothelial cells as a result the gap between endothelial cells is increased, increasing the permeability to fluids, lipids, leukocytes, monocytes, and lipoprotein particles especially low density-lipoproteins (LDL) (see Fig. 2).

Fig. 1.

Fig. 1

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Due to endothelium injury endothelial cells release proinflammatory cytokines and the permeability of endothelium is also increased as a result monocytes, T-lymphocytes, LDL, and other substances moved inside the arterial wall. The LDL is oxidized upon exposure to nitric oxide, macrophages, and some enzymes such as lipoxygenase. Monocytes present in the intima differentiated into macrophages which begin to take oxidized LDL present in the intima. Macrophages retain the lipids which they have taken up and as the density of lipids increases these macrophages are referred as foam cells which will die due to apoptosis but the lipids will accumulate in the intima resulting in the blockage of coronary arteries.

Fig. 2.

Fig. 2

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Biogenesis of miRNA involved the transcription 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 incorporated 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.

The LDL moves inside to arterial wall and undergoes oxidation upon exposure to nitric oxide, macrophages, and some enzymes such as lipoxygenase. Monocytes migrated to the intima and differentiated into macrophages which begins to take oxidized LDL already present in the intima. Macrophages retain the lipids which they have taken up and as the density of lipids increases these macrophages are referred as foam cells which will die due to apoptosis but the lipids will accumulate in the intima resulting in the blockage of coronary arteries [9].

Many factors have a role in the pathogenesis of coronary artery disease (CAD) such as the neurotrophin (NT) family including brain-derived neurotrophic(BDNF) and nerve growth factor NT-3 which plays an essential role in the growth, maintenance, survival, and death of central and peripheral neurons [10]. NTS and their receptors are also expressed in atherosclerosis lesions because it has been observed that in cultured smooth muscle cells, BDNF enhances the activity of NAD(P)H oxidase and superoxide generation because oxygen radicals activate matrix metalloproteinase [11]. The oxidative stress by BDNF induced the instability of atherosclerotic plaque hence the expression level of BDNF was high in the coronary artery of patients who has unstable angina pectoris(UAP). Abnormal protein metabolism is another risk factor for the development of CAD in genetically susceptible people, especially in those societies in which methionine consumption is high as it contributes to endothelial cell damage in the main areas of the vascular system [12]. C-reactive protein(CRP) which were initially used as a clinical biomarker for the diagnosis of infection because its production by hepatocytes increases during the acute phase of infection CRP has the main role in the precipitation of C- polysaccharide of pneumococcal cell wall but recent research showed that CRP is another risk factor for the development CAD because the production of CRP is closely related to the enzyme NAD(P)H oxidase(enzyme has a role in the production of reactive oxygen species ROS) as well CRP also directly enhance the production of NAD(P)H p22phox, as a result, the production of ROS increased in smooth muscles of coronary arteries. Any abnormality 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 production of vasodilators such as nitric oxide (NO) and vasoconstrictive such as thromboxane (TXA2). Besides vasodilators NO also has antithrombotic, 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 diabetes mellitus. Diabetes mellitus type 2 patients have two-threefold high chances of coronary artery diseases than the normal population [14]. Hypertension is also an important factor in the development of CAD which may be caused due to serum cholesterols, triglyceride, adiposity, sugar level, alcohol intake, and heart rate [15]. Familial hypercholesterolemia (FH) is a dominant common autosomal abnormality and the risk of premature coronary artery disease is ten to twenty times higher than in the normal population [16]. Like other risk factors, different types of miRNA also have a role in the pathophysiology of coronary artery disease.

2. MicroRNA biogenesis and its functions

MicroRNAs are the class of non-coding small RNA, size range from 17 to 25 nucleotides that regulate gene expression at the post-transcriptional level [17]. More than 2000 different types of miRNAs have been identified in humans which regulate the expression of about 60% of genes since the discovery of the first miRNA in 1993 [18,19]. MicroRNA gene is transcribed by RNA polymerase 2 formed stem-like structure called pri-miRNA (primary transcripts) about 100–120 nucleotides long, DGCR8 and Drosha cut some region of pri-miRNA at a specific location, as a result, pre-miRNA will produce about 70 nucleotides long, for further processing pre-miRNA is transported to the cytoplasm through exportin 5 proteins, in the cytoplasm, the dicer will cut pre-miRNA at two opposite direction and remove the hairpin-like structure as a result miRNA:miRNA* duplex is formed having 2 overhang nucleotides at 3′ end and monophosphate at both 5'ends. The miRNA:miRNA duplex is then incorporated into an RNA-inducing silencing complex(RISC) which is consists of multiple proteins such as 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 physiological activities such as cell migration, cell proliferation, and cell differentiation [20]. miRNAs are also having an important role in the development of different types of diseases such as atherosclerosis lesions, 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 inflammatory 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 specific stimuli, and activating the cell signaling pathway as result physiological changes occur that enable the cell to tolerate and recover from environmental stresses. Physiological changes usually involve repression 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 (environmental agents or infection) [26]. Cell signaling, differentiation, proliferation, and survival pathways play important roles in the regulation of many cellular activities such as cell apoptosis [27]. Any abnormality 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 regulators 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, angiogenesis, 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, promoting 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 macrophage 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 functions [36], therefore, MAP3K10 play important role in the atherosclerosis 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 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 increase in PIK3R2 and SPRED1 expression [38]. A recent study has found that miRNA-126 is down-regulated in CAD patients [39].

Fig. 3.

Fig. 3

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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 expression 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.

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 experiments 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 remodeling [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 process 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 patients via NF-kB cell signalling pathway [45].

Fig. 4.

Fig. 4

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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.

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 diseases involve an inflammatory response. Moreover, the severity of CAD and atherosclerosis increased when NLR family pyrin 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 expression [52]. The main characteristics of senescent injured endothelial cells are an increase in inflammatory proteins, a reduction in cell proliferation 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 dysfunctioning 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/reperfusion injury [55]. Ischemic preconditioning (IPC), is a powerful endogenous 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 fibroblast 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 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].

Fig. 5.

Fig. 5

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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 production of pro-inflammatory cytokines.

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 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 inflammatory response [64]. It has been demonstrated that miRNA-29b is associated with many biological processes and has a role in the development 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, downregulation 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 pathways 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 inflammatory 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 inflammatory 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 minimized the severity of atherosclerosis and altered atherosclerotic plaque [74,75]. Many studies have confirmed that miRNA-146a/b regulates 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 chromosome 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 activation of TLR4 cell signaling pathway takes place, therefor any abnormality 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].

Fig. 6.

Fig. 6

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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 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 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.

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 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, triggering 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 patients 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].

Fig. 7.

Fig. 7

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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.

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 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 coronary 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].

Fig. 8.

Fig. 8

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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, induces 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.

4. Conclusion

Cell signaling pathways play an important role in many cellular activities 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 regulation of cell signaling pathways leads to many diseases such as Parkinson'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 filaments, 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 process 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 individuals 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 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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