Victoria Johnson Research Laboratories

Richmond, VA, United States

Victoria Johnson Research Laboratories

Richmond, VA, United States
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Marchetti C.,Virginia Commonwealth University | Marchetti C.,Victoria Johnson Research Laboratories | Marchetti C.,University of Rome Tor Vergata | Toldo S.,Virginia Commonwealth University | And 17 more authors.
Journal of Cardiovascular Pharmacology | Year: 2015

Background: Sterile inflammation resulting from myocardial injury activates the NLRP3 inflammasome and amplifies the inflammatory response mediating further damage. Methods: 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. 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 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). Conclusions: Pharmacological inhibition of the NLRP3 inflammasome limits cell death and LV systolic dysfunction after ischemic and nonischemic injury in the mouse. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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