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Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy
Inflammatory cardiomyopathy covers a group of diseases characterized by inflammation and dysfunction of the heart muscle. The immunosuppressive agents such as prednisolone, azathioprine and cyclosporine are modestly effective treatments, but a molecular rationale underpinning such therapy or the dev...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973371/ https://www.ncbi.nlm.nih.gov/pubmed/33746983 http://dx.doi.org/10.3389/fimmu.2021.640837 |
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author | Singh, Kamayani Fang, Hai Davies, Graham Wright, Benjamin Lockstone, Helen Williams, Richard O. Ciháková, Daniela Knight, Julian C. Bhattacharya, Shoumo |
author_facet | Singh, Kamayani Fang, Hai Davies, Graham Wright, Benjamin Lockstone, Helen Williams, Richard O. Ciháková, Daniela Knight, Julian C. Bhattacharya, Shoumo |
author_sort | Singh, Kamayani |
collection | PubMed |
description | Inflammatory cardiomyopathy covers a group of diseases characterized by inflammation and dysfunction of the heart muscle. The immunosuppressive agents such as prednisolone, azathioprine and cyclosporine are modestly effective treatments, but a molecular rationale underpinning such therapy or the development of new therapeutic strategies is lacking. We aimed to develop a network-based approach to identify therapeutic targets for inflammatory cardiomyopathy from the evolving myocardial transcriptome in a mouse model of the disease. We performed bulk RNA sequencing of hearts at early, mid and late time points from mice with experimental autoimmune myocarditis. We identified a cascade of pathway-level events involving early activation of cytokine and chemokine-signaling pathways that precede leucocyte infiltration and are followed by innate immune, antigen-presentation, complement and cell-adhesion pathway activation. We integrated these pathway events into a network-like representation from which we further identified a 50-gene subnetwork that is predominantly induced during the course of autoimmune myocardial inflammation. We developed a combinatorial attack strategy where we quantify network tolerance to combinatorial node removal to determine target-specific therapeutic potential. We find that combinatorial attack of Traf2, Nfkb1, Rac1, and Vav1 disconnects 80% of nodes from the largest network component. Two of these nodes, Nfkb1 and Rac1, are directly targeted by prednisolone and azathioprine respectively, supporting the idea that the methodology developed here can identify valid therapeutic targets. Whereas Nfkb1 and Rac1 removal disconnects 56% of nodes, we show that additional removal of Btk and Pik3cd causes 72% node disconnection. In conclusion, transcriptome profiling, pathway integration, and network identification of autoimmune myocardial inflammation provide a molecular signature applicable to the diagnosis of inflammatory cardiomyopathy. Combinatorial attack provides a rationale for immunosuppressive therapy of inflammatory cardiomyopathy and provides an in silico prediction that the approved therapeutics, ibrutinib and idelalisib targeting Btk and Pik3cd respectively, could potentially be re-purposed as adjuncts to immunosuppression. |
format | Online Article Text |
id | pubmed-7973371 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79733712021-03-20 Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy Singh, Kamayani Fang, Hai Davies, Graham Wright, Benjamin Lockstone, Helen Williams, Richard O. Ciháková, Daniela Knight, Julian C. Bhattacharya, Shoumo Front Immunol Immunology Inflammatory cardiomyopathy covers a group of diseases characterized by inflammation and dysfunction of the heart muscle. The immunosuppressive agents such as prednisolone, azathioprine and cyclosporine are modestly effective treatments, but a molecular rationale underpinning such therapy or the development of new therapeutic strategies is lacking. We aimed to develop a network-based approach to identify therapeutic targets for inflammatory cardiomyopathy from the evolving myocardial transcriptome in a mouse model of the disease. We performed bulk RNA sequencing of hearts at early, mid and late time points from mice with experimental autoimmune myocarditis. We identified a cascade of pathway-level events involving early activation of cytokine and chemokine-signaling pathways that precede leucocyte infiltration and are followed by innate immune, antigen-presentation, complement and cell-adhesion pathway activation. We integrated these pathway events into a network-like representation from which we further identified a 50-gene subnetwork that is predominantly induced during the course of autoimmune myocardial inflammation. We developed a combinatorial attack strategy where we quantify network tolerance to combinatorial node removal to determine target-specific therapeutic potential. We find that combinatorial attack of Traf2, Nfkb1, Rac1, and Vav1 disconnects 80% of nodes from the largest network component. Two of these nodes, Nfkb1 and Rac1, are directly targeted by prednisolone and azathioprine respectively, supporting the idea that the methodology developed here can identify valid therapeutic targets. Whereas Nfkb1 and Rac1 removal disconnects 56% of nodes, we show that additional removal of Btk and Pik3cd causes 72% node disconnection. In conclusion, transcriptome profiling, pathway integration, and network identification of autoimmune myocardial inflammation provide a molecular signature applicable to the diagnosis of inflammatory cardiomyopathy. Combinatorial attack provides a rationale for immunosuppressive therapy of inflammatory cardiomyopathy and provides an in silico prediction that the approved therapeutics, ibrutinib and idelalisib targeting Btk and Pik3cd respectively, could potentially be re-purposed as adjuncts to immunosuppression. Frontiers Media S.A. 2021-03-05 /pmc/articles/PMC7973371/ /pubmed/33746983 http://dx.doi.org/10.3389/fimmu.2021.640837 Text en Copyright © 2021 Singh, Fang, Davies, Wright, Lockstone, Williams, Ciháková, Knight and Bhattacharya. http://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 | Immunology Singh, Kamayani Fang, Hai Davies, Graham Wright, Benjamin Lockstone, Helen Williams, Richard O. Ciháková, Daniela Knight, Julian C. Bhattacharya, Shoumo Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy |
title | Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy |
title_full | Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy |
title_fullStr | Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy |
title_full_unstemmed | Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy |
title_short | Transcriptomic Analysis of Inflammatory Cardiomyopathy Identifies Molecular Signatures of Disease and Informs in silico Prediction of a Network-Based Rationale for Therapy |
title_sort | transcriptomic analysis of inflammatory cardiomyopathy identifies molecular signatures of disease and informs in silico prediction of a network-based rationale for therapy |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973371/ https://www.ncbi.nlm.nih.gov/pubmed/33746983 http://dx.doi.org/10.3389/fimmu.2021.640837 |
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