Cardiomyocyte Apoptosis after Antiviral WIN 54954 Treatment in Murine Coxsackievirus B3 Myocarditis

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Abstract
Objective : Cardiomyocyte apoptosis (CA) is known to occur in experimental coxsackievirus B3 (CVB3) myocarditis. However, the mechanisms of CA induction are not well known. In this study we investigate the role of direct viral induction of CA in CVB3 myocarditis. Design : A/J mice were infected with the Woodruff strain of CVB3 and treated with WIN 54954 for 5 days thereafter. WIN 54954, a compound that inhibits early events of picornavirus infection, is known to dramatically reduce mortality in murine CVB3 myocarditis without abrogating systemic or myocardial inflammation. Presence of viral RNA ( in situ hybridization), CA (TUNEL method) and histopathology were studied in transverse ventricular sections at day 7 post infection ( n = 8 treated and n = 8 non-treated). Results : The proportion of cardiomyocytes containing viral RNA was 89% lower in WIN 54954 treated mice when compared with non-treated mice (0.29 - 0.56% vs 2.76 - 1.65%, p = 0.003). Treatment also reduced the amount of CA by 52% compared with non-treated mice (0.20 - 0.06% vs 0.42 - 0.06%, p < 0.001). The reduction of CA by WIN treatment did not result in any increase of necrosis, in fact treatment reduced the area of necrotic lesions by 77% (2.51 - 1.64% vs 11.10 - 8.76%, p = 0.028). Conclusion : Taking the results of the reduced CA, necrosis and viral RNA with no effect on inflammation into account, our findings suggest the importance of direct viral effect in cardiomyocyte damage by both apoptosis and necrosis in CVB3 myocarditis.