Pharmacologic Inhibition of the NLRP3 Inflammasome Preserves Cardiac Function After Ischemic and Nonischemic Injury in the Mouse.

Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage. We used 2 experimental models of ischemic injury (acute myocardial infarction [AMI] with and without reperfusion) and a model of nonischemic injury due to doxorubicin 10 mg/kg to determine whether the NLRP3 inflammasome preserved cardiac function after injury. Treatment with the NLRP3 inflammasome inhibitor in the reperfused AMI model caused a significant reduction in infarct size measured at pathology or as serum cardiac troponin I level (-56% and -82%, respectively, both P < 0.001) and preserved left ventricular fractional shortening (LVFS, 31 ± 2 vs. vehicle 26% ± 1%, P = 0.003). In the non-reperfused AMI model, treatment with the NLRP3 inhibitor significantly limited LV systolic dysfunction at 7 days (LVFS of 20 ± 2 vs. 14% ± 1%, P = 0.002), without a significant effect on infarct size. In the doxorubicin model, a significant increase in myocardial interstitial fibrosis and a decline in systolic function were seen in vehicle-treated mice, whereas treatment with the NLRP3 inhibitor significantly reduced fibrosis (-80%, P = 0.001) and preserved systolic function (LVFS 35 ± 2 vs. vehicle 27% ± 2%, P = 0.017). Pharmacological inhibition of the NLRP3 inflammasome limits cell death and LV systolic dysfunction after ischemic and nonischemic injury in the mouse.