PTEN is a multifunctional tumor suppressor whose major function is mediated via its lipid phosphatase activity. We first identified a potential binding site for mouse miR-222 and PTEN through TargetScan. ![]() ![]() We next investigated the effect of miRNA-222 on VMC. Our data suggest that ADAR1 bound tightly to Dicer in the mouse VMC model and H9c2cells infected with CBV3, suggesting that the interaction is direct. Coimmunoprecipitation between ADAR1 and Dicer was performedto determine whether ADAR1 protein contributes to the regulation of Dicer. Hence, we considered it reasonable to test the hypothesis that the elevated expression of ADAR1p150 has an effect on Dicer protein in the pathology of this disease. In our study, the elevated expression of ADAR1p150 waspredominantly localized in the cytoplasm of cardiac myocytes, the same location as Dicer, which produces mature miRNAs. The evidence that ADAR/Dicer promotes miRNA processing was revealed. Dicer, an endoribonuclease of the RNase III family, regulates the maturation of most miRNAs and, thus, has a significant role in numerous biological events. Similar results were found in cardiac cell lines infected with CVB3. The results of our study showed that ADAR1p150 expression in VMC was elevated, and the major part of immunostaining was localized in the cytoplasm. Since it has a potentially lethal outcome, it is imperative to further understand the mechanisms underpinning its development so as to devise novel and effective therapeutics. Therefore, CVB-induced VMC is not an unusual disease. Symptomless myocarditis may induce severe electrical dysfunction in the heart, and may even be life-threatening, particularly during exertion, which may explain the sudden death of young and vigorous individuals. This indicates that >97% of patients with lethal myocarditis do not have clinical presentations. Consistent with this, another study identified acute myocarditis as the cause of death at a rate of ~1.5% in a total of 2560 autopsies but was suspected in only one of the cases in the clinic. The prevalence of acute myocarditis identified through routine necropsy is significantly higher than that through clinical diagnosis, and the possible explanation for this discrepancy is that only a certain percentage of individuals with acute myocarditis develop easily observable clinical manifestations. CVB3 induces VMC either through inflammatory mechanisms or through a direct cytopathic effect (CPE). Coxsackievirus B3 (CVB3), belonging to the Picornaviridae family of genus Enterovirus, is regarded as the most common infectious pathogen responsible for VMC and the subsequent pathogenesis of dilated cardiomyopathy (DCM). It has been well documented that viral myocarditis (VMC) is a primary cause of sudden death and heart failure in young adults. Our work reveals a previously unknown role of ADAR1p150 in gene expression in VMC. Our findings suggest that ADAR1p150 plays a key role in complexing with Dicer and promoting the expression of miRNA-222, the latter of which suppresses the expression of the target gene PTEN during VMC. In cultured cells, miR-222 suppressed PTEN expression. By using a bioinformatics tool, we found a potential binding site of miRNA-222 on the PTEN gene’s 3′-UTR, suggesting that miRNA-222 might play a regulatory role. Among the target genes of miRNA-222, the expression of phosphatase-and-tensin (PTEN) protein was significantly reduced in VMC. In addition, the expression of miRNA-222 was promoted by ADAR1p150/Dicer. miRNA-222, which is involved in many cardiac diseases, is highly expressed in cardiomyocytes in VMC. Coimmunoprecipitation verified that ADAR1p150 forms a complex with Dicer in VMC. VMC mouse cardiomyocytes showed significantly higher expression of ADAR1p150 compared to the control samples. In this study, we examined the expression of ADAR1p150 and its role in viral myocarditis (VMC) in a mouse model. However, the role of ADAR1p150 in vascular disease remains unclear. ADAR1 is involved in a variety of pathological conditions including inflammation, cancer, and the host defense against viral infections. Adenosine deaminases acting on RNA (ADAR) are enzymes that regulate RNA metabolism through post-transcriptional mechanisms.
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