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

Marchetti, Carlo PhD*,†,‡; Toldo, Stefano PhD*,†; Chojnacki, Jeremy BS§; Mezzaroma, Eleonora PhD; Liu, Kai PhD§; Salloum, Fadi N. PhD*; Nordio, Andrea MD*,†; Carbone, Salvatore MS*,†; Mauro, Adolfo Gabriele MS*,†; Das, Anindita PhD*; Zalavadia, Ankit A. BS; Halquist, Matthew S. PhD; Federici, Massimo MD; Van Tassell, Benjamin W. PharmD*,†,‖; Zhang, Shijun PhD§; Abbate, Antonio MD, PhD*,†

Journal of Cardiovascular Pharmacology: July 2015 - Volume 66 - Issue 1 - p 1–8
doi: 10.1097/FJC.0000000000000247
Drugs in the Pipeline

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.

*VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA;

Victoria Johnson Research Laboratories, Richmond, VA;

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;

Departments of §Medicinal Chemistry;

Pharmacotherapy and Outcome Studies, and

Pharmaceutics Virginia Commonwealth University, Richmond, VA.

Reprints: Antonio Abbate, MD, PhD, VCU Pauley Heart Center, Virginia Commonwealth University, Box 980281, 1200 East Broad St, Richmond, VA 23298 (e-mail: aabbate@vcu.edu).

S. Toldo, E. Mezzaroma, F. N. Salloum, B. W. Van Tassell, and A. Abbate are supported by grants from the American Heart Association. S. Zhang is supported by an NIH R01 grant (AG041161). B. W. Van Tassell, A. Abbate, and S. Zhang are supported by a grant from Virginia Innovation Partnership.

The authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org).

Received November 14, 2014

Accepted February 25, 2015

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