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Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction

In this study, we addressed the functional significance of co-operative DNA binding of the cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) in an experimental murine model of acute myocardial infarction (MI). STAT1 knock-in mice expressing a phenylalani...

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Autores principales: Doudin, Asmma, Riebeling, Theresa, Staab, Julia, Menon, Priyanka Rajeev, Lühder, Fred, Wirths, Oliver, Vinkemeier, Uwe, Ivetic, Aleksandar, Meyer, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10008942/
https://www.ncbi.nlm.nih.gov/pubmed/36923955
http://dx.doi.org/10.3389/fcvm.2023.975012
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author Doudin, Asmma
Riebeling, Theresa
Staab, Julia
Menon, Priyanka Rajeev
Lühder, Fred
Wirths, Oliver
Vinkemeier, Uwe
Ivetic, Aleksandar
Meyer, Thomas
author_facet Doudin, Asmma
Riebeling, Theresa
Staab, Julia
Menon, Priyanka Rajeev
Lühder, Fred
Wirths, Oliver
Vinkemeier, Uwe
Ivetic, Aleksandar
Meyer, Thomas
author_sort Doudin, Asmma
collection PubMed
description In this study, we addressed the functional significance of co-operative DNA binding of the cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) in an experimental murine model of acute myocardial infarction (MI). STAT1 knock-in mice expressing a phenylalanine-to-alanine substitution at position 77 in the STAT1 amino-terminal domain were examined for the early clinical effects produced by ligation of the left anterior descending coronary artery (LAD), an established model for MI. The F77A mutation has been previously reported to disrupt amino-terminal interactions between adjacent STAT1 dimers resulting in impaired tetramerization and defective co-operative binding on DNA, while leaving other protein functions unaffected. Our results demonstrate that a loss of STAT1 tetramer stabilization improves survival of adult male mice and ameliorates left ventricular dysfunction in female mice, as determined echocardiographically by an increased ejection fraction and a reduced left intra-ventricular diameter. We found that the ratio of STAT3 to STAT1 protein level was higher in the infarcted tissue in knock-in mice as compared to wild-type (WT) mice, which was accompanied by an enhanced infiltration of immune cells in the infarcted area, as determined by histology. Additionally, RNA sequencing of the infarcted tissue 24 h after LAD ligation revealed an upregulation of inflammatory genes in the knock-in mice, as compared to their WT littermates. Concomitantly, genes involved in oxidative phosphorylation and other metabolic pathways showed a significantly more pronounced downregulation in the infarcted tissue from STAT1(F77A/F77A) mice than in WT animals. Based on these results, we propose that dysfunctional STAT1 signalling owing to a lack of oligomerisation results in a compensatory increase in STAT3 expression and promotes early infiltration of immune cells in the infarcted area, which has beneficial effects on left ventricular remodelling in early MI following LAD ligation.
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spelling pubmed-100089422023-03-14 Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction Doudin, Asmma Riebeling, Theresa Staab, Julia Menon, Priyanka Rajeev Lühder, Fred Wirths, Oliver Vinkemeier, Uwe Ivetic, Aleksandar Meyer, Thomas Front Cardiovasc Med Cardiovascular Medicine In this study, we addressed the functional significance of co-operative DNA binding of the cytokine-driven transcription factor STAT1 (signal transducer and activator of transcription 1) in an experimental murine model of acute myocardial infarction (MI). STAT1 knock-in mice expressing a phenylalanine-to-alanine substitution at position 77 in the STAT1 amino-terminal domain were examined for the early clinical effects produced by ligation of the left anterior descending coronary artery (LAD), an established model for MI. The F77A mutation has been previously reported to disrupt amino-terminal interactions between adjacent STAT1 dimers resulting in impaired tetramerization and defective co-operative binding on DNA, while leaving other protein functions unaffected. Our results demonstrate that a loss of STAT1 tetramer stabilization improves survival of adult male mice and ameliorates left ventricular dysfunction in female mice, as determined echocardiographically by an increased ejection fraction and a reduced left intra-ventricular diameter. We found that the ratio of STAT3 to STAT1 protein level was higher in the infarcted tissue in knock-in mice as compared to wild-type (WT) mice, which was accompanied by an enhanced infiltration of immune cells in the infarcted area, as determined by histology. Additionally, RNA sequencing of the infarcted tissue 24 h after LAD ligation revealed an upregulation of inflammatory genes in the knock-in mice, as compared to their WT littermates. Concomitantly, genes involved in oxidative phosphorylation and other metabolic pathways showed a significantly more pronounced downregulation in the infarcted tissue from STAT1(F77A/F77A) mice than in WT animals. Based on these results, we propose that dysfunctional STAT1 signalling owing to a lack of oligomerisation results in a compensatory increase in STAT3 expression and promotes early infiltration of immune cells in the infarcted area, which has beneficial effects on left ventricular remodelling in early MI following LAD ligation. Frontiers Media S.A. 2023-02-27 /pmc/articles/PMC10008942/ /pubmed/36923955 http://dx.doi.org/10.3389/fcvm.2023.975012 Text en Copyright © 2023 Doudin, Riebeling, Staab, Menon, Lühder, Wirths, Vinkemeier, Ivetic and Meyer. 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 Cardiovascular Medicine
Doudin, Asmma
Riebeling, Theresa
Staab, Julia
Menon, Priyanka Rajeev
Lühder, Fred
Wirths, Oliver
Vinkemeier, Uwe
Ivetic, Aleksandar
Meyer, Thomas
Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction
title Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction
title_full Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction
title_fullStr Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction
title_full_unstemmed Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction
title_short Lack of STAT1 co-operative DNA binding protects against adverse cardiac remodelling in acute myocardial infarction
title_sort lack of stat1 co-operative dna binding protects against adverse cardiac remodelling in acute myocardial infarction
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10008942/
https://www.ncbi.nlm.nih.gov/pubmed/36923955
http://dx.doi.org/10.3389/fcvm.2023.975012
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