Pharmacologic Inhibition of the NLRP3 Inflammasome Preserves Cardiac Function After Ischemic and Nonischemic Injury in the Mouse.
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.
Carlo
C
Marchetti
Stefano
S
Toldo
Jeremy
J
Chojnacki
Eleonora
E
Mezzaroma
Kai
K
Liu
Fadi N
FN
Salloum
Andrea
A
Nordio
Salvatore
S
Carbone
Adolfo Gabriele
AG
Mauro
Anindita
A
Das
Ankit A
AA
Zalavadia
Matthew S
MS
Halquist
Massimo
M
Federici
Benjamin W
BW
Van Tassell
Shijun
S
Zhang
Antonio
A
Abbate
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D004317:Doxorubicin