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Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway
Background: NLRP3 inflammasome contributes a lot to sterile inflammatory response and pyroptosis in ischemia/reperfusion (I/R) injury. Cardiac fibroblasts (CFs) are regarded as semi-professional inflammatory cells and they exert an immunomodulatory role in heart. Iguratimod provides a protective rol...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573346/ https://www.ncbi.nlm.nih.gov/pubmed/34760889 http://dx.doi.org/10.3389/fcell.2021.746317 |
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author | Zhang, Mian Lei, Yi-shan Meng, Xiao-wen Liu, Hua-yue Li, Lin-gui Zhang, Jun Zhang, Jia-xin Tao, Wen-hui Peng, Ke Lin, Jun Ji, Fu-hai |
author_facet | Zhang, Mian Lei, Yi-shan Meng, Xiao-wen Liu, Hua-yue Li, Lin-gui Zhang, Jun Zhang, Jia-xin Tao, Wen-hui Peng, Ke Lin, Jun Ji, Fu-hai |
author_sort | Zhang, Mian |
collection | PubMed |
description | Background: NLRP3 inflammasome contributes a lot to sterile inflammatory response and pyroptosis in ischemia/reperfusion (I/R) injury. Cardiac fibroblasts (CFs) are regarded as semi-professional inflammatory cells and they exert an immunomodulatory role in heart. Iguratimod provides a protective role in several human diseases through exerting a powerful anti-inflammatory effect. However, it is still unclear whether iguratimod could alleviate myocardial I/R injury and whether inflammation triggered by NLRP3-related pyroptosis of CFs is involved in this process. Methods: Transcriptomics analysis for GSE160516 dataset was conducted to explore the biological function of differentially expressed genes during myocardial I/R. In vivo, mice underwent ligation of left anterior descending coronary artery for 30 min followed by 24 h reperfusion. In vitro, primary CFs were subjected to hypoxia for 1 h followed by reoxygenation for 3 h (H/R). Iguratimod was used prior to I/R or H/R. Myocardial infarct area, serum level of cardiac troponin I (cTnI), pathology of myocardial tissue, cell viability, lactate dehydrogenase (LDH) release, and the expression levels of mRNA and protein for pyroptosis-related molecules were measured. Immunofluorescence was applied to determine the cellular localization of NLRP3 protein in cardiac tissue. Results: During myocardial I/R, inflammatory response was found to be the most significantly enriched biological process, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling was a crucial pathway in mediating cardiac inflammation. In our experiments, pretreatment with iguratimod significantly ameliorated I/R-induced myocardial injury and H/R-induced pyroptosis of CFs, as evidenced by reduced myocardial infarct area, serum cTnI level, and LDH release in supernatants, as well as improved pathology of cardiac tissue and cell viability. Immunofluorescence analysis showed that NLRP3 was mainly localized in CFs. Moreover, iguratimod inhibited the expression of pro-inflammatory cytokines and pyroptosis-related molecules, including NLRP3, cleaved caspase-1, and GSDMD-N. Conclusion: Our results suggested that inflammatory response mediated by NOD-like receptor signaling is of vital importance in myocardial I/R injury. Iguratimod protected cardiomyocytes through reducing the cascade of inflammation in heart by inhibiting cardiac fibroblast pyroptosis via the COX2/NLRP3 signaling pathway. |
format | Online Article Text |
id | pubmed-8573346 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85733462021-11-09 Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway Zhang, Mian Lei, Yi-shan Meng, Xiao-wen Liu, Hua-yue Li, Lin-gui Zhang, Jun Zhang, Jia-xin Tao, Wen-hui Peng, Ke Lin, Jun Ji, Fu-hai Front Cell Dev Biol Cell and Developmental Biology Background: NLRP3 inflammasome contributes a lot to sterile inflammatory response and pyroptosis in ischemia/reperfusion (I/R) injury. Cardiac fibroblasts (CFs) are regarded as semi-professional inflammatory cells and they exert an immunomodulatory role in heart. Iguratimod provides a protective role in several human diseases through exerting a powerful anti-inflammatory effect. However, it is still unclear whether iguratimod could alleviate myocardial I/R injury and whether inflammation triggered by NLRP3-related pyroptosis of CFs is involved in this process. Methods: Transcriptomics analysis for GSE160516 dataset was conducted to explore the biological function of differentially expressed genes during myocardial I/R. In vivo, mice underwent ligation of left anterior descending coronary artery for 30 min followed by 24 h reperfusion. In vitro, primary CFs were subjected to hypoxia for 1 h followed by reoxygenation for 3 h (H/R). Iguratimod was used prior to I/R or H/R. Myocardial infarct area, serum level of cardiac troponin I (cTnI), pathology of myocardial tissue, cell viability, lactate dehydrogenase (LDH) release, and the expression levels of mRNA and protein for pyroptosis-related molecules were measured. Immunofluorescence was applied to determine the cellular localization of NLRP3 protein in cardiac tissue. Results: During myocardial I/R, inflammatory response was found to be the most significantly enriched biological process, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling was a crucial pathway in mediating cardiac inflammation. In our experiments, pretreatment with iguratimod significantly ameliorated I/R-induced myocardial injury and H/R-induced pyroptosis of CFs, as evidenced by reduced myocardial infarct area, serum cTnI level, and LDH release in supernatants, as well as improved pathology of cardiac tissue and cell viability. Immunofluorescence analysis showed that NLRP3 was mainly localized in CFs. Moreover, iguratimod inhibited the expression of pro-inflammatory cytokines and pyroptosis-related molecules, including NLRP3, cleaved caspase-1, and GSDMD-N. Conclusion: Our results suggested that inflammatory response mediated by NOD-like receptor signaling is of vital importance in myocardial I/R injury. Iguratimod protected cardiomyocytes through reducing the cascade of inflammation in heart by inhibiting cardiac fibroblast pyroptosis via the COX2/NLRP3 signaling pathway. Frontiers Media S.A. 2021-10-25 /pmc/articles/PMC8573346/ /pubmed/34760889 http://dx.doi.org/10.3389/fcell.2021.746317 Text en Copyright © 2021 Zhang, Lei, Meng, Liu, Li, Zhang, Zhang, Tao, Peng, Lin and Ji. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Zhang, Mian Lei, Yi-shan Meng, Xiao-wen Liu, Hua-yue Li, Lin-gui Zhang, Jun Zhang, Jia-xin Tao, Wen-hui Peng, Ke Lin, Jun Ji, Fu-hai Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway |
title | Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway |
title_full | Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway |
title_fullStr | Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway |
title_full_unstemmed | Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway |
title_short | Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway |
title_sort | iguratimod alleviates myocardial ischemia/reperfusion injury through inhibiting inflammatory response induced by cardiac fibroblast pyroptosis via cox2/nlrp3 signaling pathway |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573346/ https://www.ncbi.nlm.nih.gov/pubmed/34760889 http://dx.doi.org/10.3389/fcell.2021.746317 |
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