The Role And Mechanism Of ADAR1 In The Pathogenesis Of CVB3-induced Myocarditis

Viral myocarditis (VMC) is a common cardiovascular disease induced by virus infection. The incidence of VMC is increasing in our country, reaching 5-15% in recent years and become one of the primary causes of sudden cardiac death, especially in male under 40 years of age. VMC can be induced by a variety of virus, among which the most common one is Coxsackievirus B3 type (CVB3). There is currently no effective treatment for VMC, majorly because its pathogenic mechanism is not yet clear. Previous studies showed that in VMC myocytes are both directly damaged by virus and attacked by subsequent immune responses which lead to major injuries.Adenosine deaminase acting on RNA (ADAR1) is a RNA editing enzyme that catalyzes the C-6 deamination of adenosine (A) to generate inosine (I) in RNA substrates that possess double-stranded RNA character. There are two types of ADAR 1 in cells, one of them is p110,which is constitutively expressed. The other is ADAR1 p150, it is IFN inducible. Recent studies have indicated that ADAR1 not only participate in RNA editing, but also affect the replication of the virus through inhibiting the expression of IFNs.To determine the effect of ADAR1 in CVB3 replication and VMC progression, we first detected the expressions of each member of ADAR family during the process of VMC using a mouse VMC model established by infecting BALB/c mice with CVB3. We found that only ADARlpl50 expression changed after viral infection. Next we up-regulated or knockdown ADAR1p150 expression in mice by injecting PEI packed plasmids into mice tail veins. When we knockdown the expression of ADAR1p150, the virus loads in the heart of mice decreased, myocarditis diseases significantly reduce, and survival rate was improve. When we up regulated the expression of ADAR1p150, we found although viral loads increased in the heart of mice, inflammatory cytokine secretion reduced, and survival rate was improved in some degree. Then we delayed the injected times to alter the expression of ADAR1p150 in the mid-late phase of the disease. After we down regulated the expression of ADAR1p150,we found that inflammatory factor in the heart increased, myocarditis disease more severe, and survival rate decreased, while overexpression of ADARlp150 in mid-late phase improved myocarditis disease and reduced inflammatory cells infiltration. We found that ADAR1p150 down regulated the expression of inflammatory cytokine by inhibiting the NF-κb pathway, which results in alleviation of the disease.The above results indicated that ADAR1p150 have two roles in the CVB3 induced VMC. One is to promote the viral load of the CVB3, and the other is to suppress the expression of inflammatory cytokine through NF-κb signal pathway. The ADAR1p150 is a double-edged sword in viral myocarditis induced by CVB3, plays a different role in different stages of the disease process.