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

Journal of cardiovascular pharmacology (2015-04-29)
Carlo Marchetti, Stefano Toldo, Jeremy Chojnacki, Eleonora Mezzaroma, Kai Liu, Fadi N Salloum, Andrea Nordio, Salvatore Carbone, Adolfo Gabriele Mauro, Anindita Das, Ankit A Zalavadia, Matthew S Halquist, Massimo Federici, Benjamin W Van Tassell, Shijun Zhang, Antonio Abbate
ABSTRACT

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.

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