Résumé
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•The inflammatory enzyme MPO is a potential therapeutic target in cardiovascular diseases.•PF-1355 is an orally bioavailable mechanism-based inhibitor of MPO enzymatic activity. PF-1355 treatment successfully inhibited MPO in mouse models of myocardial infarction and ischemia reperfusion injury.•Short duration oral drug treatment for 7 days attenuated inflammation and cardiac dilation during early infarct healing. However, MPO-containing cells persisted beyond 7 days.•Prolonged 21-day treatment improved ejection fraction (∼44%) and decreased end-diastolic volume (∼53%) and left ventricular mass (∼33%) compared with untreated control subjects.•Better therapeutic effect was also achieved when treatment was started early (at 1 h) after the initial ischemic insult.
PF-1355 is an oral myeloperoxidase (MPO) inhibitor that successfully decreased elevated MPO activity in mouse myocardial infarction models. Short duration PF-1355 treatment for 7 days decreased the number of inflammatory cells and attenuated left ventricular dilation. Cardiac function and remodeling improved when treatment was increased to 21 days. Better therapeutic effect was further achieved with early compared with delayed treatment initiation (1 h vs. 24 h after infarction). In conclusion, PF-1355 treatment protected a mouse heart from acute and chronic effects of MI, and this study paves the way for future translational studies investigating this class of drugs in cardiovascular diseases.