NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction.
NLRP3-inflammasome
cardiac function
infarct size
inflammation
myocardial infarction
Journal
Biomedicines
ISSN: 2227-9059
Titre abrégé: Biomedicines
Pays: Switzerland
ID NLM: 101691304
Informations de publication
Date de publication:
28 Nov 2022
28 Nov 2022
Historique:
received:
02
07
2022
revised:
16
11
2022
accepted:
18
11
2022
entrez:
23
12
2022
pubmed:
24
12
2022
medline:
24
12
2022
Statut:
epublish
Résumé
NLRP3-inflammasome-mediated signaling is thought to significantly contribute to the extent of myocardial damage after myocardial infarction (MI). The purpose of this study was to investigate the effects of the NLRP3-inflammasome inhibitor IZD334 on cardiac damage in a pig model of myocardial infarction. Prior to in vivo testing, in vitro, porcine peripheral blood mononuclear cells and whole blood were treated with increasing dosages of IZD334, a novel NLRP3-inflammasome inhibitor, and were stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). After determination of the pharmacological profile in healthy pigs, thirty female Landrace pigs were subjected to 75 min of transluminal balloon occlusion of the LAD coronary artery and treated with placebo or IZD334 (1 mg/kg, 3 mg/kg, or 10 mg/kg once daily) in a blinded randomized fashion. In vitro, NLRP3-inflammasome stimulation showed the pronounced release of interleukin (IL)-1β that was attenuated by IZD334 (p < 0.001). In vivo, no differences were observed between groups in serological markers of inflammation nor myocardial IL-1β expression. After 7 days, the ejection fraction did not differ between groups, as assessed with MRI (placebo: 45.1 ± 8.7%, 1 mg/kg: 49.9 ± 6.1%, 3 mg/kg: 42.7 ± 3.8%, 10 mg/kg: 44.9 ± 6.4%, p = 0.26). Infarct size as a percentage of the area at risk was not reduced (placebo: 73.1 ± 3.0%, 1 mg/kg: 75.5 ± 7.3%, 3 mg/kg: 80.3 ± 3.9%, 10 mg/kg: 78.2 ± 8.0%, p = 0.21). In this pig MI model, we did not observe attenuation of the inflammatory response after NLRP3-inflammasome inhibition in vivo. Consecutively, no difference was observed in IS and cardiac function, while in vitro inhibition successfully reduced IL-1β release from stimulated porcine blood cells.
Identifiants
pubmed: 36551811
pii: biomedicines10123056
doi: 10.3390/biomedicines10123056
pmc: PMC9775177
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Hartstichting
ID : 2017T067
Références
Cardiovasc Res. 2013 Jul 1;99(1):164-74
pubmed: 23580606
Clin Med Insights Cardiol. 2016 Jun 01;10:79-84
pubmed: 27279755
JACC Basic Transl Sci. 2020 Dec 28;5(12):1225-1227
pubmed: 33427823
J Cardiovasc Pharmacol. 2015 Jul;66(1):1-8
pubmed: 25915511
Nat Rev Cardiol. 2018 Apr;15(4):203-214
pubmed: 29143812
J Cardiovasc Pharmacol. 2019 Oct;74(4):271-275
pubmed: 31356546
J Am Coll Cardiol. 2016 May 3;67(17):2050-60
pubmed: 27126533
Circ Res. 2018 Jan 19;122(2):310-318
pubmed: 29348252
J Cardiovasc Pharmacol. 2014 Apr;63(4):316-322
pubmed: 24336017
Front Immunol. 2020 Dec 08;11:599511
pubmed: 33363540
J Cardiovasc Transl Res. 2021 Feb;14(1):23-34
pubmed: 32648087
N Engl J Med. 2019 Dec 26;381(26):2497-2505
pubmed: 31733140
Circ Res. 2015 Feb 13;116(4):572-86
pubmed: 25499773
J Am Coll Cardiol. 2020 Oct 13;76(15):1774-1776
pubmed: 33032739
JACC Basic Transl Sci. 2020 Dec 09;5(12):1210-1224
pubmed: 33426377
Nat Rev Cardiol. 2014 May;11(5):255-65
pubmed: 24663091
J Clin Invest. 1985 Nov;76(5):1713-9
pubmed: 4056048
N Engl J Med. 2020 Nov 5;383(19):1838-1847
pubmed: 32865380
Int J Cardiol. 2014 Nov 15;177(1):41-3
pubmed: 25499334
N Engl J Med. 2017 Sep 21;377(12):1119-1131
pubmed: 28845751
Immunol Rev. 2020 Sep;297(1):123-138
pubmed: 32770571
Nat Rev Immunol. 2019 Aug;19(8):477-489
pubmed: 31036962
Circulation. 2011 Feb 15;123(6):594-604
pubmed: 21282498
Eur Heart J. 2017 Mar 14;38(11):828-836
pubmed: 27432019
Int J Cardiol. 2016 Apr 15;209:215-20
pubmed: 26896627
Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19725-30
pubmed: 22106299
Pharmacol Rev. 2021 Jul;73(3):968-1000
pubmed: 34117094
J Cardiovasc Pharmacol. 2019 Apr;73(4):215-222
pubmed: 30747785
Nat Rev Immunol. 2016 Jul;16(7):407-20
pubmed: 27291964
Cardiovasc Res. 2017 May 1;113(6):564-585
pubmed: 28453734
Nat Chem Biol. 2019 Jun;15(6):556-559
pubmed: 31086327
Biochem Biophys Res Commun. 2016 Jan 22;469(4):1012-20
pubmed: 26706279
J Am Coll Cardiol. 2013 Jan 29;61(4):404-410
pubmed: 23265346