Cargando…

Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling

AIMS: Pathological cardiac remodelling is characterized by cardiomyocyte (CM) hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular...

Descripción completa

Detalles Bibliográficos
Autores principales: Vigil-Garcia, Marta, Demkes, Charlotte J, Eding, Joep E C, Versteeg, Danielle, de Ruiter, Hesther, Perini, Ilaria, Kooijman, Lieneke, Gladka, Monika M, Asselbergs, Folkert W, Vink, Aryan, Harakalova, Magdalena, Bossu, Alexander, van Veen, Toon A B, Boogerd, Cornelis J, van Rooij, Eva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152696/
https://www.ncbi.nlm.nih.gov/pubmed/32717063
http://dx.doi.org/10.1093/cvr/cvaa233
_version_ 1783698648508399616
author Vigil-Garcia, Marta
Demkes, Charlotte J
Eding, Joep E C
Versteeg, Danielle
de Ruiter, Hesther
Perini, Ilaria
Kooijman, Lieneke
Gladka, Monika M
Asselbergs, Folkert W
Vink, Aryan
Harakalova, Magdalena
Bossu, Alexander
van Veen, Toon A B
Boogerd, Cornelis J
van Rooij, Eva
author_facet Vigil-Garcia, Marta
Demkes, Charlotte J
Eding, Joep E C
Versteeg, Danielle
de Ruiter, Hesther
Perini, Ilaria
Kooijman, Lieneke
Gladka, Monika M
Asselbergs, Folkert W
Vink, Aryan
Harakalova, Magdalena
Bossu, Alexander
van Veen, Toon A B
Boogerd, Cornelis J
van Rooij, Eva
author_sort Vigil-Garcia, Marta
collection PubMed
description AIMS: Pathological cardiac remodelling is characterized by cardiomyocyte (CM) hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here, we aimed for a more detailed view on molecular changes driving maladaptive CM hypertrophy to aid in the development of therapies to reverse pathological remodelling. METHODS AND RESULTS: Utilizing CM-specific reporter mice exposed to pressure overload by transverse aortic banding and CM isolation by flow cytometry, we obtained gene expression profiles of hypertrophic CMs in the more immediate phase after stress, and CMs showing pathological hypertrophy. We identified subsets of genes differentially regulated and specific for either stage. Among the genes specifically up-regulated in the CMs during the maladaptive phase we found known stress markers, such as Nppb and Myh7, but additionally identified a set of genes with unknown roles in pathological hypertrophy, including the platelet isoform of phosphofructokinase (PFKP). Norepinephrine-angiotensin II treatment of cultured human CMs induced the secretion of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and recapitulated the up-regulation of these genes, indicating conservation of the up-regulation in failing CMs. Moreover, several genes induced during pathological hypertrophy were also found to be increased in human HF, with their expression positively correlating to the known stress markers NPPB and MYH7. Mechanistically, suppression of Pfkp in primary CMs attenuated stress-induced gene expression and hypertrophy, indicating that Pfkp is an important novel player in pathological remodelling of CMs. CONCLUSION: Using CM-specific transcriptomic analysis, we identified novel genes induced during pathological hypertrophy that are relevant for human HF, and we show that PFKP is a conserved failure-induced gene that can modulate the CM stress response.
format Online
Article
Text
id pubmed-8152696
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-81526962021-05-28 Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling Vigil-Garcia, Marta Demkes, Charlotte J Eding, Joep E C Versteeg, Danielle de Ruiter, Hesther Perini, Ilaria Kooijman, Lieneke Gladka, Monika M Asselbergs, Folkert W Vink, Aryan Harakalova, Magdalena Bossu, Alexander van Veen, Toon A B Boogerd, Cornelis J van Rooij, Eva Cardiovasc Res Original Articles AIMS: Pathological cardiac remodelling is characterized by cardiomyocyte (CM) hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here, we aimed for a more detailed view on molecular changes driving maladaptive CM hypertrophy to aid in the development of therapies to reverse pathological remodelling. METHODS AND RESULTS: Utilizing CM-specific reporter mice exposed to pressure overload by transverse aortic banding and CM isolation by flow cytometry, we obtained gene expression profiles of hypertrophic CMs in the more immediate phase after stress, and CMs showing pathological hypertrophy. We identified subsets of genes differentially regulated and specific for either stage. Among the genes specifically up-regulated in the CMs during the maladaptive phase we found known stress markers, such as Nppb and Myh7, but additionally identified a set of genes with unknown roles in pathological hypertrophy, including the platelet isoform of phosphofructokinase (PFKP). Norepinephrine-angiotensin II treatment of cultured human CMs induced the secretion of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and recapitulated the up-regulation of these genes, indicating conservation of the up-regulation in failing CMs. Moreover, several genes induced during pathological hypertrophy were also found to be increased in human HF, with their expression positively correlating to the known stress markers NPPB and MYH7. Mechanistically, suppression of Pfkp in primary CMs attenuated stress-induced gene expression and hypertrophy, indicating that Pfkp is an important novel player in pathological remodelling of CMs. CONCLUSION: Using CM-specific transcriptomic analysis, we identified novel genes induced during pathological hypertrophy that are relevant for human HF, and we show that PFKP is a conserved failure-induced gene that can modulate the CM stress response. Oxford University Press 2020-07-27 /pmc/articles/PMC8152696/ /pubmed/32717063 http://dx.doi.org/10.1093/cvr/cvaa233 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Vigil-Garcia, Marta
Demkes, Charlotte J
Eding, Joep E C
Versteeg, Danielle
de Ruiter, Hesther
Perini, Ilaria
Kooijman, Lieneke
Gladka, Monika M
Asselbergs, Folkert W
Vink, Aryan
Harakalova, Magdalena
Bossu, Alexander
van Veen, Toon A B
Boogerd, Cornelis J
van Rooij, Eva
Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling
title Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling
title_full Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling
title_fullStr Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling
title_full_unstemmed Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling
title_short Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling
title_sort gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152696/
https://www.ncbi.nlm.nih.gov/pubmed/32717063
http://dx.doi.org/10.1093/cvr/cvaa233
work_keys_str_mv AT vigilgarciamarta geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT demkescharlottej geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT edingjoepec geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT versteegdanielle geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT deruiterhesther geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT periniilaria geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT kooijmanlieneke geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT gladkamonikam geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT asselbergsfolkertw geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT vinkaryan geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT harakalovamagdalena geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT bossualexander geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT vanveentoonab geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT boogerdcornelisj geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling
AT vanrooijeva geneexpressionprofilingofhypertrophiccardiomyocytesidentifiesnewplayersinpathologicalremodelling