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MicroRNA-21: A potential target approach for viral
myocarditis via multiple mechanisms
Huibo Wang a
Jun Yang a* Jian Yanga
a Department of Cardiology, the First College of Clinical Medical Sciences, China
Three Gorges University, Yichang 443000, Hubei Province, China.
* Corresponding author at: Jun Yang, Department of Cardiology, the First College of
Clinical Medical Sciences, Institute of Cardiovascular Diseases, China Three Gorges
University, Yichang 443000, Hubei Province, China. Yiling Road 183, Yichang,
443000, Hubei Province, China.
Tel.:+86-15572706505; Fax. +86(717)6482302.
E-mail address: [email protected] (Dr. Jun Yang).
Viral myocarditis (VMC) is a common cardiovascular disease (CVD) without
appropriate or effective treatment.1 The clinical manifestations of this disease range
from subclinical to sudden death. According to statistics, VMC will results in
dilated cardiomyopathy (DCM) and heart failure (HF) in up to 20% of affected
children and 50% of affected adults. Although any virus can cause VMC, but
coxsackievirus B3 (CVB3) play a critical role in the disease actually.
MicroRNAs (miRNAs) are a class of endogenous, evolutionarily conserved,
small non-protein-coding RNAs that negatively regulating gene expression by
targeting and binding to messenger RNAs (mRNAs) 3 ′ untranslated region. MiRNAs
have been reported to be important in regulating almost all biological and pathological
processes including cell proliferation, differentiation, migration and apoptosis, as well
as mediate several strategic signaling pathways in inflammation. A series of miRNAs
have been confirmed participant in the pathogenesis of VMC. Among the known
miRNAs, miR-21 has been proven to play a role in infectious and inflammatory heart
disease.The potential mechanisms for miR-21 involved in CVB3-induced VMC are
showed as follows.
1. Regulating Th-17 cell differentiation
Recently, a subset of interleukin17 (IL-17)-producing CD4+ Telper T (Th) cells
has been identified as vital participants in various inflammatory and autoimmune
diseases, including VMC. Regulating Th-17 cells differentiation is considered to be a
crucial treatment for immune disorders. Expression of the transcription factor retinoic
acid related orphan receptor (ROR) γt is required for Th17 cells differentiation and
secrete IL-17. Murugaiyan G et al indicated that the expression of miR-21 was
specifically incerased in Th17 cells. However, miR-21 deficient mice showed an
absence in Th17 cell differentiation.2 Consequently, miR-21 promotes Th17
differentiation. VMC is a T cell-mediated inflammatory and autoimmune disease. Liu
YL et al found that there is a linear correlation between the expression of
miR-21/146b and IL-17/ RORγt. They subsequently confirmed that miR-21 is
involved in the pathogenesis of VMC via increase the expression of RORγt and
regulateTh-17 cell differentiation directly.3
2. Inhibiting SPRY protein expression
Sprouty homolog (SPRY) belongs to the sprouty family， which is widely
expressed in cardiac tissue and skeletal muscles tissue. There are four SPRY
homologs (SPRY1–4) in mammals. Both of them are negative feedback regulator of
the mitogen-activated protein kinase (MAPK) signaling pathway. Marchant D et al
identified that it requires activation of extracellular signal-regulated kinase and
MAPK signaling pathway for CVB3 replication in vitro during the infection of
VMC.4 SPRY1 is a direct target of miR-21, the 3' UTR of mRNAs of which contains a
predicted miRNA-binding site with miR-21. The acatastatic expression of miR-21
inhibits SPRY protein production and resulting in the up-regulation of MAPK
signaling pathway, as well as promote CVB3 replication during the infection of VMC.
3. Inhibiting the expression of PDCD4
Programmed cell death 4 (PDCD4) was first proved as a protein up-regulated
during apoptosis and suppressed tumorigenesis, which mRNA has been identified
carrying putative miR-21 binding sites and is a direct target gene of miR-21.He J et al
found that the expression of miR-21 was significantly reduced in CVB3 infected
mice.5 They succedent confirmed that miR-21 may perform an anti-apoptotic role in
VMC by inhibiting the production of PDCD4. The function of anti-apoptosis
approaches vital improved CVB3-induced heart injury.5 Such protective feature is
opposite to the deleterious effect via regulating Th-17 cell differentiation and
inhibiting SPRY protein expression.
In conclusion, miR-21 participates in the CVB3-induced SMC via multiple
pathophysiological mechanisms. On the one hand, CVB3 infections can change the
expression of miR-21 both in the heart and plasma, which could act as diagnostic
biomarkers for VMC. On the other hand, miR-21 can also aggravate inflammatory
and autoimmune damage by regulate Th-17 cell differentiation, promoting CVB3
replication by inhibits SPRY protein expression, and anti-apoptotic by inhibits the
expression of PDCD4. Thus, miR-21 may become a potential target for the treatment
of CVB3-induced VMC in future. All in all, the outlook for the clinical application of
miR-21 for VMC is valuable and promising.
Acknowledgments
This work was supported by the National Natural Science Foundation of China
(Grant No. 81170133, 81200088 and 81470387), Master's Innovation Foundation of
China Three Gorges University (2015PY052) 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.
Conflict of interest
None
References
1. Sagar S, Liu PP, Cooper LT, Jr. Myocarditis. Lancet. 2012;379(9817):738-747.
2. Murugaiyan G, da Cunha AP, Ajay AK, Joller N, Garo LP, Kumaradevan S, et al.
MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune
encephalomyelitis. The Journal of Clinical Investigation. 2015;125(3):1069-1080.
3. Liu YL, Wu W, Xue Y, Gao M, Yan Y, Kong Q, et al. MicroRNA-21 and -146b
are involved in the pathogenesis of murine viral myocarditis by regulating TH-17
differentiation. Archives of Virology. 2013;158(9):1953-1963.
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Bosentan Enhances Viral Load via Endothelin-1 Receptor Type-A-Mediated p38
Mitogen-Activated Protein Kinase Activation While Improving Cardiac Function
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