The Role And Mechanism Study Of Dpep2 In CVB3-induced Viral Myocarditis

Viral myocarditis(VMC),a clinical common cardiovascular disease,is one of main causes for sudden death in adolescence and adults.Multiple viral infections can cause myocarditis,such as coxsackievirus,cytomegalovirus,echo virus,HIV,polio virus,adenovirus,etc.Among them,the enterovirus especially coxsackievirus B3(CVB3)is the most common.Substantial evidence indicated that both of the direct virus-mediated cell damage and the indirect immune-mediated tissue injury are the main causes of viral myocarditis.Particularly,the excessive inflammatory response is the key factor of the myocarditis pathogenesis.Macrophages are thought to be the primary infiltrated inflammatory cells in myocardium at early stage of CVB3 infection.Several studies suggest that macrophages regulate the pathogenesis of viral myocarditis through secreting inflammatory cytokines.More and more evidence indicated that the myocardial cell injury is closely related to the inflammatory cells infiltrating.Therefore,we pay much attention to the myocardial macrophages.Dpep2,a glycosylphosphatidy-linositol-anchored protein,is a metalloprotease which hydrolyzes leukotriene D4(LTD4)into leukotriene E4(LTE4).LTE4 plays an important role in human skin,digestive tract and heart inflammatory diseases.Macrophages are essencial in the pathogenesis of viral myocarditis.Thus,we focus on the role of macrophage Dpep2 in the pathogenesis of CVB3-induced viral myocarditis.In this study,we established a mouse VMC model by infecting BALB/c male mice with CVB3.We found that the expression of Dpep2 increased from day1 post infection and reached the highest on day 3,suggesting that Dpep2 might be involved in viral myocarditis.To investigate the role of Dpep2 in VMC,we down-regulated Dpep2 expression in mice by tail vein injecting PEI packaged plasmids.The results showed that when we knocked down Dpep2 expression,the survival rate was significantly reduced and myocarditis was significantly increased.However,the viral replication had no obvious change in myocardium.These were reversed when we up-regulated the Dpep2 expression in mice.Results above suggested that Dpep2 may participate in viral myocarditis through regulating inflammatory response.Furthermore,Real-time PCR result showed that Dpep2 in the cardiac macrophages was significantly up-reg ulated in VMC mice.We then generated macrophage Dpep2 conditional knockout mice.Consistently,Dpep2 deletion in macrophages significantly aggravated the CVB3-induced viral myocarditis in mice.Furthermore,the experiment in vitro confirmed that Dpep2 inhibited the expression of pro-inflammatory cytokines via NF-?B signaling in macrophages,providing a potential target for the treatment of viral myocarditis.