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Role of overexpression of miR‐425‐3p on myocardial inflammation and survival rate of mice with viral myocarditis. (A) Expression of TNF‐α in the myocardial tissues of mice measured by ELISA. (B) Expression of IL‐6 in the myocardial tissues of mic measured by ELISA. (C) Expression of IL‐12 in the myocardial tissues of mice measured by ELISA. (D) Kaplan–Meier analysis for comparing the survival rate of mice, n = 10/20 mice. The data among multiple groups were analyzed by one‐way ANOVA and Bonferroni post hoc test. *p < .05, **p < .01, ***p < .001. ANOVA, analysis of variance; ELISA, enzyme‐linked immunosorbent assay; IL, interleukin; TNF, tumor necrosis factor
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Objective
Emerging articles have profiled the relations between microRNAs and viral myocarditis. This research was unearthed to explore the capacity of miR‐425‐3p on cardiomyocyte apoptosis in mice with viral myocarditis and its mechanism.
Methods
A total of 120 mice were classified into 4 groups in a random fashion (n = 30). The mice were intrape...
Citations
... It is widely known that inflammation played a key factor in the process of VMC [1,[43][44][45]. Pyroptosis, as a kind of inflammatory cell death, plays a crucial role in defending against viral infections [46][47][48]. ...
Background
Viral myocarditis (VMC) is a disease resulting from viral infection, which manifests as inflammation of myocardial cells. Until now, the treatment of VMC is still a great challenge for clinicians. Increasing studies indicate the participation of miR-29b-3p in various diseases. According to the transcriptome sequencing analysis, miR-29b-3p was markedly upregulated in the viral myocarditis model. The purpose of this study was to investigate the role of miR-29b-3p in the progression of VMC.
Methods
We used CVB3 to induce primary cardiomyocytes and mice to establish a model of viral myocarditis. The purity of primary cardiomyocytes was identified by immunofluorescence. The cardiac function of mice was detected by Vevo770 imaging system. The area of inflammatory infiltration in heart tissue was shown by hematoxylin and eosin (H&E) staining. The expression of miR-29b-3p and DNMT3A was detected by quantitative real time polymerase chain reaction (qRT–PCR). The expression of a series of pyroptosis-related proteins was detected by western blot. The role of miR-29b-3p/DNMT3A in CVB3-induced pyroptosis of cardiomyocytes was studied in this research.
Results
Our data showed that the expression of miR-29b-3p was upregulated in CVB3-induced cardiomyocytes and heart tissues in mice. To explore the function of miR-29b-3p in CVB3-induced VMC, we conducted in vivo experiments by knocking down the expression of miR-29b-3p using antagomir. We then assessed the effects on mice body weight, histopathology changes, myocardial function, and cell pyroptosis in heart tissues. Additionally, we performed gain/loss-of-function experiments in vitro to measure the levels of pyroptosis in primary cardiomyocytes. Through bioinformatic analysis, we identified DNA methyltransferases 3A (DNMT3A) as a potential target gene of miR-29b-3p. Furthermore, we found that the expression of DNMT3A can be modulated by miR-29b-3p during CVB3 infection.
Conclusions
Our results demonstrate a correlation between the expression of DNMT3A and CVB3-induced pyroptosis in cardiomyocytes. These findings unveil a previously unidentified mechanism by which CVB3 induces cardiac injury through the regulation of miR-29b-3p/DNMT3A-mediated pyroptosis.
... During myocardial remodeling, abnormalities in collagen metabolism occur, leading to an elevation in levels of type I collagen catabolic product (ICTP), and the anabolic product (PINP). Also, MMP-9 plays a vital role in the regulation of type I collagen metabolism, while TGF-β1 accelerates the breakdown of collagen metabolism [25]. ...
Purpose: To investigate the effectiveness of sodium creatine phosphate (SCP) in pediatric viral myocarditis, and cellular immune functions. Methods: Clinical data of 83 children with viral myocarditis admitted to Dezhou Traditional Chinese Medicine Hospital, China between May 2019 and June 2021 were collected and randomly assigned to control (n = 41) and study groups (n = 42). Control group (CNG) received conventional treatment for 14 days, including intravenous drip of sodium fructose diphosphate, vitamin C, and ribavirin, with the addition of prednisone if necessary. Study group (SG) received SCP in addition to conventional treatment for 14 days. Clinical efficacy, cardiac function, inflammatory and immune markers, myocardial injury, and adverse effects at the end of treatment were determined. Results: Results indicated a significantly higher total effective rate in study group (95.24 %) compared to control group (78.05 %) (p < 0.05). Study group demonstrated significantly lower heart rates and improved cardiac output, stroke volume, and left ventricular ejection fraction after 14 days of treatment compared to control group (p < 0.05). Furthermore, study group exhibited significant reduction in levels of inflammatory markers (p < 0.05), enhanced cellular immune markers (p < 0.05), and reduced myocardial injury and remodeling markers (p < 0.05). Both groups showed similar incidence of adverse reactions. Conclusion: Sodium creatine phosphate (SCP) is effective in treating pediatric viral myocarditis, enhances cardiac function, restores cellular immune function, reduces inflammation, and minimizes myocardial damage and remodeling. There will be need to evaluate the long-term efficacy and prognosis of SCP in treating pediatric viral myocarditis in the future.
... Moreover, after injecting agomiR-425-3p into mice with VMC, it appeared that IL-6, IL-12, and TNF-α levels were lower than in mice without this intervention. Furthermore, the survival rate of VMC mice was higher in those who had received the injection of agomiR-425-3p [59]. Three studies focused directly on miR-155, which implies its pivotal role in VMC. ...
Myocarditis is an inflammatory heart disease with viruses as the most common cause. Regardless of multiple studies that have recently been conducted, the diagnostic options still need to be improved. Although endomyocardial biopsy is known as a diagnostic gold standard, it is invasive and, thus, only sometimes performed. Novel techniques of cardiac magnetic resonance are not readily available. Therapy in viral infections is based mainly on symptomatic treatment, while steroids and intravenous immunoglobulins are used in autoimmune myocarditis. The effectiveness of neither of these methods has been explicitly proven to date. Therefore, novel diagnostic and therapeutic strategies are highly needed. MiRNAs are small, non-coding molecules that regulate fundamental cell functions, including differentiation, metabolism, and apoptosis. They present altered levels in different diseases, including myocarditis. Numerous studies investigating the role of miRNAs in myocarditis have already been conducted. In this review, we discussed only the original preclinical in vivo research. We eventually included 30 studies relevant to the discussed area. The altered miRNA levels have been observed, including upregulation and downregulation of different miRNAs in the mice models of myocarditis. Furthermore, the administration of mimics or inhibitors of particular miRNAs was shown to significantly influence inflammation, morphology, and function of the heart and overall survival. Finally, some studies presented prospective advantages in vaccine development.
... On the other hand, data suggest that plasma upregulation of miRNA 155 is associated with coronary slow flow [35]. Literature on miRNAs 30b-5p, 30c-5p, 103a-5p, 140-3p, 185-5p 221-3p and 425-3p shows regulatory properties in atherosclerosis as well as cardiomyocyte apoptosis and necrosis [21,[36][37][38][39][40][41][42]. ...
Background
MicroRNAs are paramount in post transcriptional gene regulation. We investigated platelet miRNAs in patients with CAD and examined potential associations with course of left ventricular ejection fraction (LVEF%).
Materials and methods
In a first cohort, 62 MiRNAs were measured in platelets of 100 patients suffering from CAD. Expression profiles of individuals with chronic coronary syndrome (CCS) and MI were compared (CCS n = 67, MI n = 33). Also, associations between miRNA profiles and change in left ventricular ejection fraction (LVEF%) were investigated. In a second cohort of patients suffering from CCS (n = 10), MI (n = 11) or no CAD (n = 13), we measured miRNA expression in platelets, platelet supernatant and serum. This was carried out before and after in vitro platelet activation with CRP.
Results
Platelet miRNAs 103a-3p and 155-5p demonstrated higher expression in patients with CCS then in individuals with MI. Furthermore, multiple miRNAs were significantly higher expressed in matched controls compared to MI patients. 8 miRNAs showed higher expression in patients with improving LVEF% after a 1-year follow-up. In our second cohort, we found higher concentrations of 6 miRNAs in the platelet supernatant of patients with CCS, MI and no CAD after in vitro platelet activation. Most of these miRNAs showed a higher abundance in serum of MI patients as compared to CCS.
Conclusion
Several miRNAs show higher expression in platelets of CCS compared to MI. After in vitro platelet activation, a release of multiple miRNAs out of the thrombocyte was observed. Furthermore, upregulation of serum miRNAs was found in MI patients when compared to CCS patients and individuals without CAD. Hence, platelets could present a source of upregulated circulating miRNAs in MI and additionally affect course of LVEF%.
... miR-425-3p agomir prevented cardiomyocyte apoptosis and improved cardiac function by targeting transforming growth factor β1 (TGF-β1) [140]. ...
... Cardio-detrimental miRNAs and cardio-protective miRNAs are presented as red and green, respectively, with their known targets. MI, myocardial infarction; DCM, diabetic cardiomyopathy; VMCs, viral myocarditis; Dox-induced HF, doxorubicin-induced heart failure; HSP20, heat-shock protein 20; PDCD4, programmed cell death 4; YES1, YES proto-oncogene 1; SOCS2, suppressor of cytokine signaling 2; SIRT3, Sirtuin 3; PTEN, phosphatase and tensin homolog; Drp1, dynamin-related protein-1; Bak1, BCL2 antagonist/killer 1; NLRP3, OD-like receptor pyrin domain containing 3; TGFβ1, transforming growth factor beta 1; QKI, Quaking; Cab39, calcium binding protein 39; PKB, protein kinase B; Fitm2, fat storage-inducing transmembrane protein 2; Nrf2, nuclear factor (erythroid-derived 2)-like 2; TAF9b, TBP associated factor 9b. and miR-425-3p increased cardiac performance by reducing apoptosis [137,139,140]. In Dox-induced HF, miR-31-5p, miR-451, miR-143, miR-132/212, miR-208, and miR-34a increased while miR-29b, miR-146, miR-200, and miR-21 protected against apoptosis and HF [147, 149-151, 153, 154, 156-158]. ...
Cardiovascular diseases (CVDs) are the leading causes of death and disability worldwide, despite the wide diversity of molecular targets identified and the development of therapeutic methods. MicroRNAs (miRNAs) are a class of small (about 22 nucleotides) non-coding RNAs (ncRNAs) that negatively regulate gene expression at the post-transcriptional level in the cytoplasm and play complicated roles in different CVDs. While miRNA overexpression in one type of cell protects against heart disease, it promotes cardiac dysfunction in another type of cardiac cell. Moreover, recent studies have shown that, apart from cytosolic miRNAs, subcellular miRNAs such as mitochondria- and nucleus-localized miRNAs are dysregulated in CVDs. However, the functional properties of cellular- and subcellular-localized miRNAs have not been well characterized. In this review article, by carefully revisiting animal-based miRNA studies in CVDs, we will address the regulation and functional properties of miRNAs in various CVDs. Specifically, the cell–cell crosstalk and subcellular perspective of miRNAs are highlighted. We will provide the background for attractive molecular targets that might be useful in preventing the progression of CVDs and heart failure (HF) as well as insights for future studies.
... Based on the ceRNA hypothesis that circRNA can sponge miRNA, our results found that circSETBP1 and circGUCY2C could sponge ssc-miR-149 and ssc-miR-425-3p, respectively. Many studies have shown that miR-149 (Mohamed et al. 2014;Jiao et al. 2018;Lu et al. 2018;Peng et al. 2020) and miR-425-3p play an important role in regulating muscle growth and development (Li et al. 2021a). Our analysis revealed that PIK3CD and CFL1 were targets of ssc-miR-149 and ssc-miR-425-3p, respectively. ...
Circular RNA (circRNA) is a class of non-coding RNA (ncRNA) that plays an important regulatory role in various biological processes of the organisms and has a major function in muscle growth and development. However, its molecular mechanisms of how it regulates pork quality remain unclear at present. In this study, we compared the longissimus dorsi (LD) muscle expression profiles of Queshan Black (QS) and Large White (LW) pigs to explore the role of circRNAs in meat quality using transcriptome sequencing. A total of 62 differentially expressed circRNAs (DECs), including 46 up- and 16 down-regulated, 39 differentially expressed miRNAs (DEmiRNAs), including 21 up- and 18 down-regulated and 404 differentially expressed mRNAs (DEMs), including 174 up- and 230 down-regulated were identified, and most circRNAs were composed of exons. Our results indicated that the DEC parent genes and DEMs were enriched in the positive regulation of fast-twitch skeletal muscle fiber contraction, relaxation of skeletal muscle, regulation of myoblast proliferation, AMPK signaling pathway, Wnt and Jak-STAT signaling pathway. Furthermore, circSETBP1/ssc-miR-149/PIK3CD and circGUCY2C/ssc-miR-425-3p/CFL1 were selected by constructing the competitive endogenous RNA (ceRNA) regulatory network, circSETBP1, circGUCY2C, PIK3CD and CFL1 had low expression level in QS, while ssc-miR-149 and ssc-miR-425-3p had higher expression level than LW, our analysis revealed that circSETBP1, circGUCY2C, ssc-miR-149, ssc-miR-425-3p, PIK3CD and CFL1 were associated with lipid regulation, cell proliferation and differentiation, so the two ceRNAs regulatory networks may play an important role in regulating intramuscular fat (IMF) deposition, thereby affecting pork quality. In conclusion, we described the gene regulation by the circRNA–miRNA–mRNA ceRNA networks by comparing QS and LW pigs LD muscle transcriptome, and the two new circRNA-associated ceRNA regulatory networks that could help to elucidate the formation mechanism of pork quality. The results provide a theoretical basis for further understanding the genetic mechanism of meat quality formation.
... For example, miR-497-5p (Zhao et al., 2020), microRNA-150-3p (Qiu et al., 2020), miR-708-5p , and microRNA-497-5p (Liu et al., 2020a) have been shown to promote this process, while miR-30 (Zhang et al., 2020a), miR-129-5p (Yin et al., 2020), miR-128-3p , and miR-17-5p have suppressive effects. In various cell types, miR-425-3p is differentially expressed (Li et al., 2020;Ma et al., 2019), but its function in osteogenesis has not been documented. The MC3T3-E1 pre-osteoblast cell line has been widely used for in vitro osteogenesis research (Lv et al., 2017). ...
Osteoblast differentiation is a complex process that is essential for normal bone formation. A growing number of studies have shown that microRNAs (miRNAs) are key regulators in a variety of physiological and pathological processes, including osteogenesis. In this study, BMP2 was used to induce MC3T3-E1 cells to construct osteoblast differentiation cell model. Then, we investigated the effect of miR-452-3p on osteoblast differentiation and the related molecular mechanism by RT-PCR analysis, Western blot analysis, ALP activity, and Alizarin Red Staining. We found that miR-452-3p was significantly downregulated in osteoblast differentiation. Overexpression miR-452-3p (miR-452-3p mimic) significantly inhibited the expression of osteoblast marker genes RUNX2, osteopontin (OPN), and collagen type 1 a1 chain (Col1A1), and decreased the number of calcium nodules and ALP activity. In contrast, knockdown miR-452-3p (miR-452-3p inhibitor) produced the opposite effect. In terms of mechanism, we found that Smad4 may be the target of miR-452-3p, and knockdown Smad4 (si-Smad4) partially inhibited the osteoblast differentiation enhanced by miR-452-3p. Our results suggested that miR-452-3p plays an important role in osteoblast differentiation by targeting Smad4. Therefore, miR-452-3p is expected to be used in the treatment of bone formation and regeneration.
Viral myocarditis (VMC) is one of the most common acquired heart diseases in children and teenagers. However, its pathogenesis is still unclear, and effective treatments are lacking. This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes (CMCs) induced by coxsackievirus B3 (CVB3). CVB3 was utilized for inducing the VMC mouse model and cellular model. Cardiac echocardiography, left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were implemented to assess the cardiac function. In CVB3-induced VMC mice, cardiac insufficiency was observed, as well as the altered levels of ferroptosis-related indicators (glutathione peroxidase 4 (GPX4), glutathione (GSH), and malondialdehyde (MDA)). However, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) could restore the changes caused by CVB3 stimulation. Let-7a-5p was enriched in hucMSCs-exo, and the inhibitory effect of hucMSCs-exolet-7a-5p mimic on CVB3-induced ferroptosis was higher than that of hucMSCs-exomimic NC (NC: negative control). Mothers against decapentaplegic homolog 2 (SMAD2) increased in the VMC group’ while the expression of zinc-finger protein 36 (ZFP36) decreased. Let-7a-5p was confirmed to interact with SMAD2 messenger RNA (mRNA), and the SMAD2 protein interacted directly with the ZFP36 protein. Silencing SMAD2 and overexpressing ZFP36 inhibited the expression of ferroptosis-related indicators. Meanwhile, the levels of GPX4, solute carrier family 7, member 11 (SLC7A11), and GSH were lower in the SMAD2 overexpression plasmid (oe-SMAD2)+let-7a-5p mimic group than in the oe-NC+let-7a-5p mimic group, while those of MDA, reactive oxygen species (ROS), and Fe2+ increased. In conclusion, these data showed that ferroptosis could be regulated by mediating SMAD2 expression. Exo-let-7a-5p derived from hucMSCs could mediate SMAD2 to promote the expression of ZFP36, which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.
Purpose
While pediatric myocarditis incidence has increased since the coronavirus disease 2019 (COVID-19) pandemic, there remain questions regarding diagnosis, risk stratification, and optimal therapy. This review highlights recent publications and continued unanswered questions related to myocarditis in children.
Recent findings
Emergence from the COVID-19 era has allowed more accurate description of the incidence and prognosis of myocarditis adjacent to COVID-19 infection and vaccine administration as well that of multi-system inflammatory disease in children (MIS-C). As cardiac magnetic resonance technology has shown increased availability and evidence in pediatric myocarditis, it is important to understand conclusions from adult imaging studies and define the use of this imaging biomarker in children. Precision medicine has begun to allow real-time molecular evaluations to help diagnose and risk-stratify cardiovascular diseases, with emerging evidence of these modalities in myocarditis.
Summary
Recent information regarding COVID-19 associated myocarditis, cardiac magnetic resonance, and molecular biomarkers may help clinicians caring for children with myocarditis and identify needs for future investigations.
