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NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction
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 infarct...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9775177/ https://www.ncbi.nlm.nih.gov/pubmed/36551811 http://dx.doi.org/10.3390/biomedicines10123056 |
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author | Silvis, Max J. M. Demkes, Evelyne J. Timmers, Leo Arslan, Fatih de Jager, Saskia C. A. Sluijter, Joost P. G. Mosterd, Arend de Kleijn, Dominique P. V. Bosch, Lena van Hout, Gerardus P. J. |
author_facet | Silvis, Max J. M. Demkes, Evelyne J. Timmers, Leo Arslan, Fatih de Jager, Saskia C. A. Sluijter, Joost P. G. Mosterd, Arend de Kleijn, Dominique P. V. Bosch, Lena van Hout, Gerardus P. J. |
author_sort | Silvis, Max J. M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9775177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97751772022-12-23 NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction Silvis, Max J. M. Demkes, Evelyne J. Timmers, Leo Arslan, Fatih de Jager, Saskia C. A. Sluijter, Joost P. G. Mosterd, Arend de Kleijn, Dominique P. V. Bosch, Lena van Hout, Gerardus P. J. Biomedicines Article 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. MDPI 2022-11-28 /pmc/articles/PMC9775177/ /pubmed/36551811 http://dx.doi.org/10.3390/biomedicines10123056 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Silvis, Max J. M. Demkes, Evelyne J. Timmers, Leo Arslan, Fatih de Jager, Saskia C. A. Sluijter, Joost P. G. Mosterd, Arend de Kleijn, Dominique P. V. Bosch, Lena van Hout, Gerardus P. J. NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction |
title | NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction |
title_full | NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction |
title_fullStr | NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction |
title_full_unstemmed | NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction |
title_short | NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction |
title_sort | nlrp3-inflammasome inhibition with izd334 does not reduce cardiac damage in a pig model of myocardial infarction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9775177/ https://www.ncbi.nlm.nih.gov/pubmed/36551811 http://dx.doi.org/10.3390/biomedicines10123056 |
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