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

Abstract

Background Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage. Methods We used two experimental models of ischemic injury (acute myocardial infarction [AMI] with and without reperfusion) and a model of non-ischemic injury due to doxorubicin 10 mg/Kg, to determine whether the NLRP3 inflammasome preserved cardiac function after injury. Results 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 LV 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 DOX 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). Conclusion Pharmacological inhibition of the NLRP3 inflammasome limits cell death and LV systolic dysfunction following ischemic and non-ischemic injury in the mouse.

Colchicine in Acute Myocardial Infarction: “Teaching New Tricks to an Old Dog”

“…Consistent with a central role of the NALP3/NLRP3 in the inflammatory injury during ischemia-reperfusion [11,12], colchicine 1.5 mg followed by 0.5 mg 1 hour later and 0.5 mg twice daily for 5 days significantly reduced the size of the myocardial infarction in patients with ST-elevation AMI undergoing primary percutaneous coronary intervention [13] (Figures 1 and 2). …”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…Additionally, the NLRP3 inhibitor reduced LV dysfunction and remodelling in mice 1 week after permanent LAD ligation without affecting infarct scar size [137]. 16673-34-0 was also found to be effective against non-ischaemic cardiac injury (doxorubicin-induced cardiomyopathy), with a resultant decrease in fibrosis and preservation of systolic function [137]. Hence, irrespective of the precise cellular context, it may be that NLRP3 represents a useful therapeutic target for reducing post-MI injury and remodelling.…”

“…This resulted in a marked decrease in cell damage (troponin I levels) and infarct size after 24 h [136] and reduced LV dysfunction after 7 days [137]. Additionally, the NLRP3 inhibitor reduced LV dysfunction and remodelling in mice 1 week after permanent LAD ligation without affecting infarct scar size [137].…”

“…This resulted in a marked decrease in cell damage (troponin I levels) and infarct size after 24 h [136] and reduced LV dysfunction after 7 days [137]. Additionally, the NLRP3 inhibitor reduced LV dysfunction and remodelling in mice 1 week after permanent LAD ligation without affecting infarct scar size [137]. 16673-34-0 was also found to be effective against non-ischaemic cardiac injury (doxorubicin-induced cardiomyopathy), with a resultant decrease in fibrosis and preservation of systolic function [137].…”

“…Other attractive DAMP receptor targets include the inflammasome receptor NLRP3. A novel pharmacological NLRP3 inhibitor improved cardiac function in mouse models of ischaemic and non-ischaemic myocardial injury [136,137].…”