After viral infections, especially with CVB3, not only direct viral cytopathy but also activated host immune responses aggravate the deterioration of viral myocarditis during the acute phase. Through ubiquitin-proteasome system-meditated AMPK activation, MG-132, the proteasome inhibitor, inhibits viral replication, regulates mitochondrial-mediated intrinsic myocardial apoptosis, downregulates NF-κB-mediated inflammation and limits structural damage.

Coxsackievirus B3 (CVB3) is the primary cause of infectious myocarditis. Aggressive immunological activation and apoptosis of myocytes contributes to progressive dysfunction of cardiac contraction and poor prognosis. MG-132, a proteasome inhibitor, regulates mitochondrial-mediated intrinsic myocardial apoptosis and downregulates NF-κB-mediated inflammation. Here, we determined whether AMPK pathway participates in MG-132-mediated myocardial protection in viral-induced myocarditis.

Acute viral myocarditis models were established by intraperitoneal inoculation of CVB3 in male BALB/c mice. Myocarditis and age-matched control mice were administered MG-132 and/or BML-275 dihydrochloride (BML) (AMPK antagonist) intraperitoneally daily from the day following CVB3 inoculation. MG-132 improved hemodynamics and inhibited the structural remodeling of the ventricle in mice with myocarditis, while BML largely blunted these effects. TUNEL staining and immunochemistry suggested that MG-132 exerts anti-apoptotic and anti-inflammatory effects against CVB3-induced myocardial injuries. BML attenuated the effects of MG-132 on anti-apoptosis and anti-inflammation.

MG-132 modulated apoptosis and inflammation, improved hemodynamics, and inhibited the structural remodeling of ventricles in a myocarditis mouse model via regulation of the AMPK signal pathway.