Bosentan Enhances Viral Load via Endothelin-1 Receptor Type-A-Mediated p38 Mitogen-Activated Protein Kinase Activation While Improving Cardiac Function During Coxsackievirus-Induced Myocarditis

Reduced cardiac output is one of the consequences of myocarditis. Bosentan, an endothelin-1 receptor (ET1R) antagonist, could be useful to reduce cardiac afterload, preserving cardiac output. In this study, we investigated the potential therapeutic use of bosentan in an animal model of viral myocarditis. Using a mouse model of coxsackievirus B3 (CVB3)-induced myocarditis, we demonstrated preserved ejection fraction (EF) and fractional shortening (FS) by treatment with bosentan (68 +/- 5.8% EF and 40 +/- 3.7% FS for treated versus 48 +/- 2.2% EF and 25 +/- 2.6% FS for controls; P = 0.028). However, bosentan enhanced cardiac viral load (10.4 +/- 6.7% in the bosentan group versus 5.0 +/- 5.5% in control group; P = 0.02), likely through enhancement of p38 mitogen-activated protein kinase (MAPK) phosphorylation (0.77 +/- 0.40% ATF2 activation in the bosentan group versus 0.03 +/- 0.02% in controls; P = 0.0002), mediated by endothelin receptor type-A. We further demonstrate that a water soluble inhibitor of p38 MAPK, SB203580 HCl, is a potent inhibitor of virus replication in the heart (0.28% antisense viral genome stained area for 3 mg/kg dose versus 2.9% stained area for controls; P = 0.01), attenuates CVB3-induced myocardial damage (blinded cardiac histopathologic scores of 1.8 +/- 1.6 and 2.05 +/- 1.2 for the 3 mg/kg and 10 mg/kg doses, respectively, versus 3.25 +/- 1.2 for the controls), and preserves cardiac function (69 +/- 3.5% EF for 3 mg/kg dose and 71 +/- 6.7% EF for 10 mg/kg dose versus 60 +/- 1.5% EF control; P = 0.038 and P = 0.045, as compared to control, respectively). Bosentan, a prescribed vasodilator, improves cardiac function but enhances viral load and myocarditis severity through ETRA mediated p38 MAPK activation; p38 MAPK is a desirable antiviral target. Caution must be exercised during treatment of suspected infectious myocarditis with supportive vasoactive remedies. (Circ Res. 2009; 104: 813-821.)