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Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability

Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexe...

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Autores principales: Schips, Tobias G., Vanhoutte, Davy, Vo, Alexander, Correll, Robert N., Brody, Matthew J., Khalil, Hadi, Karch, Jason, Tjondrokoesoemo, Andoria, Sargent, Michelle A., Maillet, Marjorie, Ross, Robert S., Molkentin, Jeffery D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325143/
https://www.ncbi.nlm.nih.gov/pubmed/30622267
http://dx.doi.org/10.1038/s41467-018-08026-8
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author Schips, Tobias G.
Vanhoutte, Davy
Vo, Alexander
Correll, Robert N.
Brody, Matthew J.
Khalil, Hadi
Karch, Jason
Tjondrokoesoemo, Andoria
Sargent, Michelle A.
Maillet, Marjorie
Ross, Robert S.
Molkentin, Jeffery D.
author_facet Schips, Tobias G.
Vanhoutte, Davy
Vo, Alexander
Correll, Robert N.
Brody, Matthew J.
Khalil, Hadi
Karch, Jason
Tjondrokoesoemo, Andoria
Sargent, Michelle A.
Maillet, Marjorie
Ross, Robert S.
Molkentin, Jeffery D.
author_sort Schips, Tobias G.
collection PubMed
description Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability.
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spelling pubmed-63251432019-01-10 Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability Schips, Tobias G. Vanhoutte, Davy Vo, Alexander Correll, Robert N. Brody, Matthew J. Khalil, Hadi Karch, Jason Tjondrokoesoemo, Andoria Sargent, Michelle A. Maillet, Marjorie Ross, Robert S. Molkentin, Jeffery D. Nat Commun Article Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability. Nature Publishing Group UK 2019-01-08 /pmc/articles/PMC6325143/ /pubmed/30622267 http://dx.doi.org/10.1038/s41467-018-08026-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Schips, Tobias G.
Vanhoutte, Davy
Vo, Alexander
Correll, Robert N.
Brody, Matthew J.
Khalil, Hadi
Karch, Jason
Tjondrokoesoemo, Andoria
Sargent, Michelle A.
Maillet, Marjorie
Ross, Robert S.
Molkentin, Jeffery D.
Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability
title Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability
title_full Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability
title_fullStr Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability
title_full_unstemmed Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability
title_short Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability
title_sort thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325143/
https://www.ncbi.nlm.nih.gov/pubmed/30622267
http://dx.doi.org/10.1038/s41467-018-08026-8
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