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PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease

Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prev...

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Autores principales: Patel, Vaibhav B., Zhabyeyev, Pavel, Chen, Xueyi, Wang, Faqi, Paul, Manish, Fan, Dong, McLean, Brent A., Basu, Ratnadeep, Zhang, Pu, Shah, Saumya, Dawson, John F., Pyle, W. Glen, Hazra, Mousumi, Kassiri, Zamaneh, Hazra, Saugata, Vanhaesebroeck, Bart, McCulloch, Christopher A., Oudit, Gavin Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300608/
https://www.ncbi.nlm.nih.gov/pubmed/30568254
http://dx.doi.org/10.1038/s41467-018-07812-8
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author Patel, Vaibhav B.
Zhabyeyev, Pavel
Chen, Xueyi
Wang, Faqi
Paul, Manish
Fan, Dong
McLean, Brent A.
Basu, Ratnadeep
Zhang, Pu
Shah, Saumya
Dawson, John F.
Pyle, W. Glen
Hazra, Mousumi
Kassiri, Zamaneh
Hazra, Saugata
Vanhaesebroeck, Bart
McCulloch, Christopher A.
Oudit, Gavin Y.
author_facet Patel, Vaibhav B.
Zhabyeyev, Pavel
Chen, Xueyi
Wang, Faqi
Paul, Manish
Fan, Dong
McLean, Brent A.
Basu, Ratnadeep
Zhang, Pu
Shah, Saumya
Dawson, John F.
Pyle, W. Glen
Hazra, Mousumi
Kassiri, Zamaneh
Hazra, Saugata
Vanhaesebroeck, Bart
McCulloch, Christopher A.
Oudit, Gavin Y.
author_sort Patel, Vaibhav B.
collection PubMed
description Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prevents biomechanical stress-induced adverse cytoskeletal remodeling and heart failure in mice. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Accordingly, loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity.
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spelling pubmed-63006082018-12-21 PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease Patel, Vaibhav B. Zhabyeyev, Pavel Chen, Xueyi Wang, Faqi Paul, Manish Fan, Dong McLean, Brent A. Basu, Ratnadeep Zhang, Pu Shah, Saumya Dawson, John F. Pyle, W. Glen Hazra, Mousumi Kassiri, Zamaneh Hazra, Saugata Vanhaesebroeck, Bart McCulloch, Christopher A. Oudit, Gavin Y. Nat Commun Article Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prevents biomechanical stress-induced adverse cytoskeletal remodeling and heart failure in mice. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Accordingly, loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity. Nature Publishing Group UK 2018-12-19 /pmc/articles/PMC6300608/ /pubmed/30568254 http://dx.doi.org/10.1038/s41467-018-07812-8 Text en © The Author(s) 2018 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
Patel, Vaibhav B.
Zhabyeyev, Pavel
Chen, Xueyi
Wang, Faqi
Paul, Manish
Fan, Dong
McLean, Brent A.
Basu, Ratnadeep
Zhang, Pu
Shah, Saumya
Dawson, John F.
Pyle, W. Glen
Hazra, Mousumi
Kassiri, Zamaneh
Hazra, Saugata
Vanhaesebroeck, Bart
McCulloch, Christopher A.
Oudit, Gavin Y.
PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease
title PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease
title_full PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease
title_fullStr PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease
title_full_unstemmed PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease
title_short PI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease
title_sort pi3kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300608/
https://www.ncbi.nlm.nih.gov/pubmed/30568254
http://dx.doi.org/10.1038/s41467-018-07812-8
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