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Abstract
BackgroundThe P38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in CVB3-induced diseases. We previously demonstrated microRNA-21 has potential inhibitory effect on the MAP2K3 which locates upstream of P38 MAPK and was upregulated in mouse hearts upon CVB3 infection. However, the effect and underlying mechanism of miRNA-21 on CVB3 infection remain unclear.MethodsWe detected continuous changes of cellular miRNA-21 and P38 MAPK proteins expression profiling post CVB3 infection in vitro within 12 h. P38 MAPK signaling was inhibited by the specific inhibitor, small interfering RNA and miRNA-21 mimic in vitro, CVB3 replication, cell apoptosis rate and proliferation were detected. Viral load in the mice heart, cardiomyocyte apoptosis rate and histological of the heart were also detected in the mice model of viral myocarditis pretreated with miRNA-21-lentivirus.ResultsWe observed significant upregulation of miRNA-21 expression followed by suppression of the MAP2K3/P38 MAPK signaling in CVB3-infected Hela cells. The inactivation of the MAP2K3/P38 MAPK signaling by P38 MAPK specific inhibitor, small interfering RNA against MAP2K3, or miRNA-21 overexpression significantly inhibited viral progeny release from CVB3-infected cells. Mechanistically, when compared with control miRNA, miRNA-21 showed no effect on capsid protein VP1 expression and viral load within host cells, while significantly reversing CVB3-induced caspase-3 activation and cell apoptosis rate, further promoting proliferation of infected cells, which indicates the inhibitory effect of miRNA-21 on CVB3 progeny release. In the in vivo study, when compared with control miRNA, miRNA-21 pretreatment remarkably inactivated the MAP2K3/P38 MAPK signaling in mice and protected them against CVB3 infection as evidenced by significantly alleviated cell apoptosis rate, reduced viral titers, necrosis in the heart as well as by remarkably prolonged survival time.ConclusionsmiRNA-21 were reverse correlated with P38 MAPK activation post CVB3 infection, miRNA-21 overexpression significantly inhibited viral progeny release and decreased myocytes apoptosis rate in vitro and in vivo, suggesting that miRNA-21 may serve as a potential therapeutic agent against CVB3 infection through targeting the MAP2K3/P38 MAPK signaling.
Highlights
The P38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in Coxsackievirus B3 (CVB3)-induced diseases
CVB3 infection in HeLa cells activates miR‐21 expression, which targets the MAP2K3 3′UTRIn our previous study, we performed expression profiling of cellular miRNAs in the heart of CVB3-infected mice and determined that miRNA-21 is overexpressed in the acute stage [22]
CVB3 infection in HeLa cells leads to activation of P38 MAPK, which is downstream of MAP2K3 [12, 13]
Summary
The P38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in CVB3-induced diseases. CVB3 infection may lead to acute heart failure and sudden death due to direct cytopathic effects induced by viral replication in the early phase of infection [1, 2]. Accumulating evidence has demonstrated that numerous viruses, including CVB3, activate the p38 MAPK subfamily to facilitate inflammatory responses, apoptosis, and viral replication in infected cells [7,8,9,10,11]. The p38 MAPK inhibitor SB203580 suppresses CVB3-induced Hela cell apoptosis and viral progeny release, suggesting that the p38 MAPK signaling is essential for cytopathic effects and life cycle of CVB3 in infected cells [12]. Targeting the MAP2K3/p38 MAPK signaling would be a promising therapeutic approach against CVB3 infection
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