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The emerging role of micro-ribonucleic acids in coxsackievirus
B3-induced viral myocarditis
Running title: MiRNAs in CVB3-induced VCM
Hui-Bo Wang, MM, MD
Jun Yang*, MM, MD.
a Department of Cardiology, the First College of Clinical Medical Sciences, China Three Gorges
University, Yichang 443000, Hubei Province, China,
b Institute of Cardiovascular Diseases, China Three Gorges University, Yichang 443000, Hubei
Province, China.
*Corresponding author at: Department of Cardiology, the First College of Clinical Medical
Sciences, China Three Gorges University, Yichang 443000, Hubei Province, China.
E-mail address: [email protected] (Dr. Jun Yang).
Abstract: Viral myocarditis (VMC) is a common cardiovascular disease, which causing heart
failure and sudden death in young, previously healthy individuals. Coxsackievirus B3 (CVB3) is
the most important cause of VMC. But there is no reliable and effective treatment for
CVB3-induced VMC presently. Micro-ribonucleic acids (microRNAs, miRNAs) are small
non-coding RNAs that can post-transcriptionally regulate gene expression by interacting with the
target messenger RNAs (mRNAs). Numerous studies have confirmed that miRNAs take part in the
pathological and physiological mechanism of VMC. This article reviews the latest insights in the
identification of miRNAs and the potential mechanisms for their roles in CVB3-induced VMC
Keywords MicroRNAs; Viral myocarditis; Coxsackievirus B3; MiRNA-based therapeutics
1. Introduction
Viral myocarditis (VMC) is a common cardiovascular disease (CVD), which is the main
cause at least in developed countries acute myocarditis. 1 Without effective therapies, VMC will
develop chronic disease and that chronic myocarditis progresses to dilated cardiomyopathy (DCM)
and congestive heart failure (CHF) in up to 20% of affected children and 50% of affected adults.2
Although any microbial agent can cause myocarditis. Virtually coxsackievirus B3 (CVB3) are
considered the most common cause of VMC nowadays.3 However, virus-specific preventive or
therapeutic procedure available for VMC are presently lacking.4
Micro-ribonucleic acids (microRNAs, miRNAs) are small （ 21 ~ 25nt ） evolutionarily
conserved non-protein-coding RNAs that can post-transcriptionally regulate gene expression by
interacting with the target messenger RNAs (mRNAs).5 Numerous studies have confirmed that
miRNAs play a significant role in the infection of Enterovirus (such as enterovirus 71, CVB3 and
other enterovirus).6 The purpose of the present review is to focus on recent data regarding miRNAs
that take part in the pathological and physiological mechanism of CVB3-induced VMC (Table 1).
Table 1:MiRNAs in in CVB3-induced viral myocarditis
microRNAs
miR-1
Targets
Function: protective(+)
or destructive(-)
References
Cx43
-
16
miR-10a
CVB3 ORF 3D-coding region
-
19
miR-342-5p
CVB3 ORF 2C-coding region
+
20
miR-126
ERK1/2 and Wnt/βcatenin
-
25
miR-203
ZFP-148
-
28
+
30
miR-221/222
ETS1/2, IRF2, BCL2L11, et al
miR-21
Th17,SPRY1,and PDCD4
+/-
34,37,40
miR-146
Th17
-
34
miR-155 ,
NF-κB
+
43
miR-148a
NF-κB
+
43
miR-590-3p
NF-κB
+
44
miR-214
AIP4
-
46
miR-23a
CCL7
+
49
miR-374
SOCS1
+
49,50
2. The biology of miRNAs
MiRNAs have become one of the hottest research areas of the past two decades since it was
discovery by Lee et al. in 1993.7 They are a kind of small single-stranded, evolutionarily
conserved non-protein-coding RNAs produced naturally by eukaryotes cells.8 MiRNAs are
encoded from individual miRNA genes or introns of protein coding genes, which initially
transcribed to long primary transcripts (pri-miRNAs) by the RNA-polymerase II in the nucleus.
Subsequently, the majority of them are spliced by the Drosha RNase III-cofactors complex to
pre-miRNAs, which are transported out by exportin-5 form nucleus to cytosol, where it is then
processed into a mature miRNA/miRNA* duplex by Dicer RNA-processing ribonuclease III. Only
one strand of this is duplex preferentially retained and ultimately becomes the mature single
miRNA (Fig. 1).9-12 The other one (miRNA*) is degraded afterwards
Fig.1 MicroRNA synthesis
The guide single stranded of the mature miRNA (functional) is usually incorporated into the
RNA-induced silencing complex (RISC), where RISC-microRNA complex specifically targets
mRNAs 3′-untranslated region (UTR) and promote mRNA silencing by degradation of mRNA or by
blocking protein translation.10,11,13 A series of studies shows that each individual miRNA regulates
multiple mRNA targets within a regulatory network, thus affecting various fundamental cellular
pathway and governing biologic function, such as cell proliferation, differentiation, migration and
apoptosis.8,10
3. MiRNAs in coxsackievirus B3-induced VMC
MiRNAs play a significant role in the infection of enterovirus such as enterovirus 71, CVB 3,
polioviruses, rhinoviruses and other enterovirus.6 Numbers studies have focused on miRNAs
related to CVB3 infection because CVB3 is a common virus of VMC. Zhang et al analyzed
expression leval of miRNAs and mRNAs from CVB3-infected mice heart tissues. They identified
several miRNAs (such as miR-21, miR-23a, miR-29a*, miR-146a and miR-374) are involved in
regulating vital innate immune and antiviral pathways. 13 Now, I have summarized the latest
miRNAs take part in the pathogenesis of CVB3-induced VMC as follows.
3.1 Regulate the expression of connexin 43
MiR-1 is specifically expressed in adult cardiac tissues and skeletal muscle tissues, which has
been found to be up-regulated in various CVD.14 Yang et al found that miR-1 is up-expressed in
individuals with coronary atherosclerosis disease (CAD) and exacerbates arrhythmogenesis.15 Xu
H F et al confirmed that miR-1 also participate in the pathogenesis of VMC.16
Intercellular communication can occur directly between neighbour cells electrical coupling
required synchronized cardiac contraction via gap junctions (GJ).17 Connexin 43 (Cx43) is the
most widely expressed Connexin, which the main GJ in ventricular myocardium that allows
electrical coupling and intercellular communication between proximal cardiomyocytes.17 Cx43
responsible for the appropriate function of the cardiac conduction system and plays a significant
role in the pathophysiology of VMC. Xu H F et al confirmed that the expression of Cx43 was
greatly diminished in VMC mice than that in healthy mice heart.16 Altered expression of Cx43
might impair propagation of the electrical impulse and cause arrhythmias. They also investigated
miR-1 is characteristically up-regulated in VMC and causes suppression of Cx43 measured by
real-time PCR and western blotting.16 Thus, miR-1 might participate VMC by represses Cx43
expression via post-transcriptional repression.
3.2 Regulate CVB3 biosynthesis
CVB is the major pathogen of human VMC that can lead to DCM and CHF. CVB genome
composed of three parts: 3′-UTR, 5′-UTR and single open reading frame (ORF).18 The mainly
function of CVB genome 5′-UTR is guiding the processes of virus translation and replication. CVB
genome can be a direct target of cellular miRNAs via ORF (encodes a polyprotein that is
processed into non-structural proteins and the capsid proteins).18 MiR-10a*, comes from miR-10a/
miR-10a* duplex, is not only a passenger RNA molecule but also a functional RNA molecule in the
cells.19 Lei T et al found that the expression of miR-10a* in the myocardial tissue of 3-week-old
mice is lower than that of adult mice. Compared to the fact that the neonatal mice is more sensitive
to the CVB3 cardiac infection. MiR-10a* may relate to the CVB3 infection and VMC. They
subsequently confirmed that miR-10a* augmented CVB3 biosynthesis via target the viral ORF
3D-coding region. 19 In addition to miR-10a*, their team also found potential miR-342-5p targets
in the CVB3 genom and inhibit CVB3 biosynthesis by targeting its ORF 2C-coding region.20 Thus
the function of miR-10a* and miR-342-5p are opposite. MiR-10a* augmented CVB3 biosynthesis,
however miR-342-5p inhibit it.
CVB3 infection can result systematical changes of host gene transcription and translation, as
well as depressing of the extracellular signal regulated protein kinases (ERK1/2) signaling
pathway (primary pillars of signal transduction networks during CVB3 infection).21,22 The
inhibition of ERK1/2 activation attenuated viral replication induced by CVB3 infection via
phosphorylation modification, which cause cell death subsequently.23 What’s more, ERK1/2 can
also regulates CVB3 enter into the host cells. 24MiR-126 is enriched in myocardium. Ye X et al
found that the expression of miR-126 is up-regulated during CVB3 infection. 25 They subsequently
confirmed that miR-126 promoted CVB3 replication and virus-induced cell death via cross-talk
between ERK1/2 and Wnt/β-catenin pathways by targeting EVH1 domain containing 1 (SPRED1) ,
lipoprotein receptor-related protein 6(LRP6) and Wnt-responsive Cdc42 homolog 1(WRCh1).25
Thus, miR-126 is an evildoer in the pathogenesis of VMC.
Zinc finger protein-148 (ZFP-148), a transcription factor, inhibit viral replication via
interfere the viral RNA synthesis.26 ZFP-148 is an ideal target of miR-203. Reports shows that
silencing of ZFP-148 by miR-203 led to enhance cell growth, which involved in the pathogenesis
of many diseases. 27 What’s more, the function of enhance cell growth created an advantageous
conditions for CVB3 replication and damaged the target cells. 28 Therefore, miR-203 participates
in the pathogenesis of CVB3-induced myocarditis via targeting of ZFP-148 and promoting virus
replication.
MiR-221 and miR-222 are clustered closely and co-regulated their common promoters and
regulatory sequences.29 They are significantly elevated during VMC caused by CVB3. Corsten M et
al indicated that overexpression of miR-221 and miR-222 inhibited cardiac viral load, abbreviated
the viraemic state, as well as strongly suppressed cardiac injury and inflammation, whereas
knockdown of this miR-221/-222 cluster augmented viral replication.30
3.3 Regulate TH-17 differentiation
Th17 cell is a kind of unique CD4+ Telper T (Th) cells that produce and secrete interleukin17
(IL-17). 31They are participates in the pathogenesis of various inflammatory and autoimmune
diseases. 32 Regulating TH-17 differentiation are considered to be a critical diagnosis and
treatment for immune disorders.31 RORγt is a splice variant of the RORγ gene，which has been
proved to be a key regulator for TH-17 differentiation. 33 VMC is a T cell mediated inflammatory
and autoimmune disease. Liu YL et al detected the expression of miR-21 and miR-146b mRNAs
were significant increased in CVB3-induced VMC, whereas miR-451 mRNA was decreased. There
is a linear correlation between the expression of miR-21/146b and IL-17/ RORγt.34 Their team
subsequently confirmed that miR-21 and miR-146b are involved in the pathogenesis of murine
VMC via increase the expression of RORγt and directly regulateTH-17 differentiation. Such
function can be suppressed by Ets-1 (an inhibitor of RORγ).34However, the relationship between
miR-451 and VMC need further research to clarify.
3.4 Inhibit sprouty homolog protein expression
Sprouty homolog (SPRY) protein family (contains SPRY1-4) are widely expressed in cardiac
tissue and skeletal muscles tissue. 35 It is a negative feedback regulator of the mitogen-activated
protein kinase (MAPK) signaling pathway. 36 The abnormal expression of miR-21 inhibits SPRY
protein production via directly target SPRY mRNA 3' UTR miRNA-binding site, such process
resulting in the up-regulation of MAPK expression. SPRY adjust the collagen gene express and
regulates a series of function such as cell growth, differentiation, transformation, proliferation,
cell survival and apoptosis.37 What’s more, the up-regulation of MAPK expression leads to
myocardial fibrosis and cardiac remodeling during the disease of VMC, which aggravate the
myocardial damage. Thus, miR-21 may contribute to the pathogenic progression of VMC to DCM
via inhibits SPRY protein production and activate MAPK signal pathway.37
3.5 Regulate the expression of programmed cell death 4
Programmed cell death 4 (PDCD4) was first detected as a protein up-regulated during
apoptosis, which involved in apoptosis and tumor suppression.38 PDCD4 mRNA has been
identified carrying putative miR-21 binding sites. Research shows that miR-21 regulate the
expression of PDCD4 and take part in several biological activities (such as apoptosis,
proliferation and anchorage independent growth).39 He J et al found that miR-21 targeting
PDCD4 and perform an anti-apoptotic role in CVB3-induced VMC.40 Such function is opposite to
the effect of miR-21 regulate TH-17 differentiation and inhibits SPRY protein expression. Further
studies on the miR-21 participate in the pathogenesis of CVB3-induced VMC should be conducted
such as to test whether it is a protective miRNAs or not.
3.6 Regulate nuclear factor kappa B pathway
Nuclear factor kappa B (NF-κB), one central pathway of intracellular signaling, play an
important role in the VMC development by the function of its pro-inflammation and release many
proinflammatory cytokines such as interleukin-6 (IL-6).41 It has been identified that miRNAs
mediate several key signaling pathways in NF-κB induced inflammation. 42 Bao et al identified that
the expression of miR-155 and miR-148a was significantly increased in myocardial tissues of
patients with VMC. 43 They subsequently confirmed that miR-155 and miR-148a is directly target
RelA gene and modulate immune response to CVB3 by repress NF-κB pathway, through which can
improved mice survival rate when CVB3 infected.43 Similarly, miR-590-3p is a potential novel
NF-κB-related miRNA, which directly targets the NF-κB p50 subunit (a key factor of the canonical
NF-κB pathway) and inhibit p50 expression, NF-κB activity in vivo.44 In conclusion, miR-155,
miR-148a and miR-590-3p may reduces the lesion area and improves the cardiac by repress
NF-κB pathway during VMC.
Atrophin-1 interacting protein 4 (AIP4) is also called ITCH, which is an NF-κB signaling
suppressor.45
MiR-214 was found to be up-regulated both in the myocardial cells and plasma
during CVB3-induced VMC. Chen ZG et al indicated that miR-214 contributed to the adverse
inflammatory response to CVB3 infection via targeting ITCH and promote activating NF-κB
signaling. 46
3.6 Regulate the expression of chemokine (C-C motif) ligand 7
Chemokine (C-C motif) ligand 7 (CCL7) is an important pro-inflammatory factor that
increasing the expression of CCL7 can aggravate myocardial inflammation.47,48 MiR-23a can
regulate immune and inflammatory responses to protect myocardium function and promote tissue
repair via directly target CCL7 mRNA and decreased the expression of CCL7.49
3.8 Activate JAK- STAT pathway
The Janus kinase-(JAK-) signal transducer and activator of transcription (STAT) pathway
participate in various cellular processes such as inflammation, apoptosis, cell-cycle regulation and
development. 50 It is required for the early innate defense against CVB3 infection during VMC. 50
Suppressor of cytokine signaling (SOCS) family members are negatively regulate CVB3-induced
JAK and STAT signaling. However, such function could be restrained by miR-374 through directly
target SOCS1 mRNA .49
4 Conclusion
Emerging evidence has demonstrated that miRNAs play a critical role in the CVB3-induced
VMC via various physiopathologic mechanism. On the one hand, CVB3 infections can change the
expression of miRNAs both in the cardiomyocytes and plasma, which could act as diagnostic
biomarkers for VMC. On the one hand, some miRNAs can regulate the expression of CVB3 gene
directly or regulate CVB3 replication indirectly by targeting a mediator. Thus, miRNAs have a
potential therapeutic role. However,there is still incomplete understanding about miRNAs involved
in VMC. Future research is warranted to explore miRNAs in the diagnosisand treatment of
CVB3-induced VMC. In short, the outlook for the clinical application of VMC-related miRNAs is
valuable and promising.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant No.
81170133 to J. Yang; Grant No. 81200088,81470387 to J. Yang), and the Natural Science
Foundation of Yichang city, China (Grant No.A12301-01) as well as Hubei Province' s
Outstanding Medical Academic Leader program, China.
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