The present study found that serum H2S level, H2S production rate, CSE mRNA and CSE protein levels were increased in CVB3-induced myocarditis. DL-proparglygylcine (PAG), an irreversible CSE inhibitor, decreased the infected myocardium titers on postinfection day 4, while NaHS, a H2S donor, alleviated myocardial injury and necrosis, inflammatory cell infiltration and interstitial edema on postinfection day 10. These data reveal that the CSE/H2S pathway is upregulated in the heart in a murine model of CVB3-induced myocarditis and that inhibition of endogenous H2S is beneficial to treatment early in the disease while administration of exogenous H2S is protective to infected myocardium during the later stage. Published by Elsevier Inc.