Antonio Abbate, Stephano Toldo
Abstract
Reperfusion is effective in reducing ischemic injury in acute myocardial infarction (AMI). Ischemia, however, triggers a secondary injury, known as reperfusion injury, contributing to the overall infarct size. Multiple mechanisms are being explored to favorably modify the effects of reperfusion injury. We hypothesize that inhibition of the Nod-like Receptor Protein-3 (NLRP3) inflammasome limits infarct size following myocardial ischemia/reperfusion (I/R), by inhibiting the inflammatory component of the reperfusion injury. We induced AMI in adult mice by transient ligation of the left anterior descending coronary artery for 30 or 75 minutes. We tested 3 different strategies to inhibit the NLRP3 inflammasome: a newly designed small molecule specifically inhibiting the inflammasome (NLPR3inh), plasma derived alpha-1 antitrypsin (AAT) shown to inhibit the NLRP3 inflammasome, and a synthetic oligopeptide (SP16) designed to reproduce the C-terminal peptide of AAT. Infarct size was measured at 1, 3 and 24 hours and expressed as % of area at risk. Infarct size increased with duration of ischemia from 43±4% with 30 minutes to 65±3% with 75 minutes if ischemia (P<0.001) showing a wavefront of ischemic injury. After 30 minutes of ischemia, however, infarct size progressively increased from 1 to 24 hours after reperfusion (11±2% at 1 hour, 30±5% at 3 hours and 43±4% at 24 hours) showing a wavefront of reperfusion injury. Administration of the NLRP3inh, AAT or SP16 given immediately at reperfusion or within 30 minutes after reperfusion following 30 or 75 minutes of ischemia significantly reduced infarct size at 24 hours (-56%, -44%, -55%, respectively, vs vehicle, all P<0.01). Pharmacological inhibition of the NLRP3 inflammasome within 1 hour of reperfusion limits the secondary inflammatory injury and infarct size following myocardial ischemia-reperfusion in the mouse. Pharmacological interventions alone or in conjunction with other interventions show promise to significantly further improve outcome post myocardial infarction.