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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. 4. Marchant D, Dou Y, Luo HL, Garmaroudi FS, McDonough JE, Si X, et al. Bosentan Enhances Viral Load via Endothelin-1 Receptor Type-A-Mediated p38 Mitogen-Activated Protein Kinase Activation While Improving Cardiac Function During Coxsackievirus-Induced Myocarditis. Circulation Research. 2009; 104(6):813-821. 5. He J, Yue Y, Dong C, Xiong S. MiR-21 confers resistance against CVB3-induced myocarditis by inhibiting PDCD4-mediated apoptosis. Clinical and investigative medicine Medecine clinique et experimentale. 2013;36(2):E103-111.