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The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling

Myocardial injury is associated with inflammation and fibrosis. Cardiac myosin-binding protein-C (cMyBP-C) is cleaved by µ-calpain upon myocardial injury, releasing C0-C1f, an N-terminal peptide of cMyBP-C. Previously, we reported that the presence of C0-C1f is pathogenic within cardiac tissue and i...

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Autores principales: Yogeswaran, Athiththan, Troidl, Christian, McNamara, James W., Wilhelm, Jochen, Truschel, Theresa, Widmann, Laila, Aslam, Muhammad, Hamm, Christian W., Sadayappan, Sakthivel, Lipps, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230336/
https://www.ncbi.nlm.nih.gov/pubmed/34073556
http://dx.doi.org/10.3390/cells10061326
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author Yogeswaran, Athiththan
Troidl, Christian
McNamara, James W.
Wilhelm, Jochen
Truschel, Theresa
Widmann, Laila
Aslam, Muhammad
Hamm, Christian W.
Sadayappan, Sakthivel
Lipps, Christoph
author_facet Yogeswaran, Athiththan
Troidl, Christian
McNamara, James W.
Wilhelm, Jochen
Truschel, Theresa
Widmann, Laila
Aslam, Muhammad
Hamm, Christian W.
Sadayappan, Sakthivel
Lipps, Christoph
author_sort Yogeswaran, Athiththan
collection PubMed
description Myocardial injury is associated with inflammation and fibrosis. Cardiac myosin-binding protein-C (cMyBP-C) is cleaved by µ-calpain upon myocardial injury, releasing C0-C1f, an N-terminal peptide of cMyBP-C. Previously, we reported that the presence of C0-C1f is pathogenic within cardiac tissue and is able to activate macrophages. Fibroblasts also play a crucial role in cardiac remodeling arising from ischemic events, as they contribute to both inflammation and scar formation. To understand whether C0-C1f directly modulates fibroblast phenotype, we analyzed the impact of C0-C1f on a human fibroblast cell line in vitro by performing mRNA microarray screening, immunofluorescence staining, and quantitative real-time PCR. The underlying signaling pathways were investigated by KEGG analysis and determined more precisely by targeted inhibition of the potential signaling cascades in vitro. C0-C1f induced pro-inflammatory responses that might delay TGFβ-mediated myofibroblast conversion. TGFβ also counteracted C0-C1f-mediated fibroblast activation. Inhibition of TLR4 or NFκB as well as the delivery of miR-146 significantly reduced C0-C1f-mediated effects. In conclusion, C0-C1f induces inflammatory responses in human fibroblasts that are mediated via TRL4 signaling, which is decreased in the presence of TGFβ. Specific targeting of TLR4 signaling could be an innovative strategy to modulate C0-C1f-mediated inflammation.
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spelling pubmed-82303362021-06-26 The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling Yogeswaran, Athiththan Troidl, Christian McNamara, James W. Wilhelm, Jochen Truschel, Theresa Widmann, Laila Aslam, Muhammad Hamm, Christian W. Sadayappan, Sakthivel Lipps, Christoph Cells Article Myocardial injury is associated with inflammation and fibrosis. Cardiac myosin-binding protein-C (cMyBP-C) is cleaved by µ-calpain upon myocardial injury, releasing C0-C1f, an N-terminal peptide of cMyBP-C. Previously, we reported that the presence of C0-C1f is pathogenic within cardiac tissue and is able to activate macrophages. Fibroblasts also play a crucial role in cardiac remodeling arising from ischemic events, as they contribute to both inflammation and scar formation. To understand whether C0-C1f directly modulates fibroblast phenotype, we analyzed the impact of C0-C1f on a human fibroblast cell line in vitro by performing mRNA microarray screening, immunofluorescence staining, and quantitative real-time PCR. The underlying signaling pathways were investigated by KEGG analysis and determined more precisely by targeted inhibition of the potential signaling cascades in vitro. C0-C1f induced pro-inflammatory responses that might delay TGFβ-mediated myofibroblast conversion. TGFβ also counteracted C0-C1f-mediated fibroblast activation. Inhibition of TLR4 or NFκB as well as the delivery of miR-146 significantly reduced C0-C1f-mediated effects. In conclusion, C0-C1f induces inflammatory responses in human fibroblasts that are mediated via TRL4 signaling, which is decreased in the presence of TGFβ. Specific targeting of TLR4 signaling could be an innovative strategy to modulate C0-C1f-mediated inflammation. MDPI 2021-05-26 /pmc/articles/PMC8230336/ /pubmed/34073556 http://dx.doi.org/10.3390/cells10061326 Text en © 2021 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
Yogeswaran, Athiththan
Troidl, Christian
McNamara, James W.
Wilhelm, Jochen
Truschel, Theresa
Widmann, Laila
Aslam, Muhammad
Hamm, Christian W.
Sadayappan, Sakthivel
Lipps, Christoph
The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling
title The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling
title_full The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling
title_fullStr The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling
title_full_unstemmed The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling
title_short The C0-C1f Region of Cardiac Myosin Binding Protein-C Induces Pro-Inflammatory Responses in Fibroblasts via TLR4 Signaling
title_sort c0-c1f region of cardiac myosin binding protein-c induces pro-inflammatory responses in fibroblasts via tlr4 signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230336/
https://www.ncbi.nlm.nih.gov/pubmed/34073556
http://dx.doi.org/10.3390/cells10061326
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