Inhibition of the NLRP3 inflammasome limits the inflammatory injury following myocardial ischemia–reperfusion in the mouse

Successful reperfusion is the most effective strategy to reduce ischemic injury in acute myocardial infarction (AMI). Ischemic injury, however, also triggers a secondary ischemia-independent injury, known as reperfusion injury, contributing to the overall infarct size. 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.CD-1 male mice underwent transient ligation of the left anterior descending coronary artery for 30 or 75min followed by reperfusion. Infarct size was measured at 1, 3 and 24h. A NLRP3 inflammasome inhibitor (NLRP3inh) or vehicle was administrated immediately at time of reperfusion or with a delay of 1 or 3h of reperfusion.A time-dependent increase in infarct size was measured at 1, 3, and 24h after reperfusion (11±2%, 30±5% and 43±4% of the area at risk respectively; P<0.001 for trend). NLRP3 myocardial expression was significantly increased at 24h and 6h vs 3h (P<0.01). Administration of the NLRP3inh at reperfusion did not reduce infarct size at 3h, while it significantly reduced infarct size at 24h (-56% vs vehicle, P<0.01). The NLRP3inh given 1h after reperfusion also significantly decreased caspase-1 activity and infarct size measured at 24h, whereas the NLRP3inh did not when given with a delay of 3h.Pharmacological inhibition of the NLRP3 inflammasome within 1h of reperfusion limits the secondary inflammatory injury and infarct size following myocardial ischemia-reperfusion in the mouse.