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Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice

PIEZO1 is a subunit of mechanically-activated, nonselective cation channels. Gain-of-function PIEZO1 mutations are associated with dehydrated hereditary stomatocytosis (DHS), a type of anaemia, due to abnormal red blood cell function. Here, we hypothesised additional effects on the heart. Consistent...

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Autores principales: Bartoli, Fiona, Evans, Elizabeth L., Blythe, Nicola M., Stewart, Leander, Chuntharpursat-Bon, Eulashini, Debant, Marjolaine, Musialowski, Katie E., Lichtenstein, Laeticia, Parsonage, Gregory, Futers, T. Simon, Turner, Neil A., Beech, David J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997529/
https://www.ncbi.nlm.nih.gov/pubmed/35406763
http://dx.doi.org/10.3390/cells11071199
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author Bartoli, Fiona
Evans, Elizabeth L.
Blythe, Nicola M.
Stewart, Leander
Chuntharpursat-Bon, Eulashini
Debant, Marjolaine
Musialowski, Katie E.
Lichtenstein, Laeticia
Parsonage, Gregory
Futers, T. Simon
Turner, Neil A.
Beech, David J.
author_facet Bartoli, Fiona
Evans, Elizabeth L.
Blythe, Nicola M.
Stewart, Leander
Chuntharpursat-Bon, Eulashini
Debant, Marjolaine
Musialowski, Katie E.
Lichtenstein, Laeticia
Parsonage, Gregory
Futers, T. Simon
Turner, Neil A.
Beech, David J.
author_sort Bartoli, Fiona
collection PubMed
description PIEZO1 is a subunit of mechanically-activated, nonselective cation channels. Gain-of-function PIEZO1 mutations are associated with dehydrated hereditary stomatocytosis (DHS), a type of anaemia, due to abnormal red blood cell function. Here, we hypothesised additional effects on the heart. Consistent with this hypothesis, mice engineered to contain the M2241R mutation in PIEZO1 to mimic a DHS mutation had increased cardiac mass and interventricular septum thickness at 8–12 weeks of age, without altered cardiac contractility. Myocyte size was greater and there was increased expression of genes associated with cardiac hypertrophy (Anp, Acta1 and β-MHC). There was also cardiac fibrosis, increased expression of Col3a1 (a gene associated with fibrosis) and increased responses of isolated cardiac fibroblasts to PIEZO1 agonism. The data suggest detrimental effects of excess PIEZO1 activity on the heart, mediated in part by amplified PIEZO1 function in cardiac fibroblasts.
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spelling pubmed-89975292022-04-12 Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice Bartoli, Fiona Evans, Elizabeth L. Blythe, Nicola M. Stewart, Leander Chuntharpursat-Bon, Eulashini Debant, Marjolaine Musialowski, Katie E. Lichtenstein, Laeticia Parsonage, Gregory Futers, T. Simon Turner, Neil A. Beech, David J. Cells Article PIEZO1 is a subunit of mechanically-activated, nonselective cation channels. Gain-of-function PIEZO1 mutations are associated with dehydrated hereditary stomatocytosis (DHS), a type of anaemia, due to abnormal red blood cell function. Here, we hypothesised additional effects on the heart. Consistent with this hypothesis, mice engineered to contain the M2241R mutation in PIEZO1 to mimic a DHS mutation had increased cardiac mass and interventricular septum thickness at 8–12 weeks of age, without altered cardiac contractility. Myocyte size was greater and there was increased expression of genes associated with cardiac hypertrophy (Anp, Acta1 and β-MHC). There was also cardiac fibrosis, increased expression of Col3a1 (a gene associated with fibrosis) and increased responses of isolated cardiac fibroblasts to PIEZO1 agonism. The data suggest detrimental effects of excess PIEZO1 activity on the heart, mediated in part by amplified PIEZO1 function in cardiac fibroblasts. MDPI 2022-04-02 /pmc/articles/PMC8997529/ /pubmed/35406763 http://dx.doi.org/10.3390/cells11071199 Text en © 2022 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
Bartoli, Fiona
Evans, Elizabeth L.
Blythe, Nicola M.
Stewart, Leander
Chuntharpursat-Bon, Eulashini
Debant, Marjolaine
Musialowski, Katie E.
Lichtenstein, Laeticia
Parsonage, Gregory
Futers, T. Simon
Turner, Neil A.
Beech, David J.
Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice
title Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice
title_full Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice
title_fullStr Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice
title_full_unstemmed Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice
title_short Global PIEZO1 Gain-of-Function Mutation Causes Cardiac Hypertrophy and Fibrosis in Mice
title_sort global piezo1 gain-of-function mutation causes cardiac hypertrophy and fibrosis in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997529/
https://www.ncbi.nlm.nih.gov/pubmed/35406763
http://dx.doi.org/10.3390/cells11071199
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