Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.11/7315 |
Resumo: | Secreted phospholipase A2-IIA (sPLA2-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA2-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA2-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA2-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA2-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA2-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA2-IIA. In conclusion, sPLA2-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects. |
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Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis linkCardiac fibroblastEpidermal growth factor receptorFibrosisLysyl oxidaseMyocarditisSecreted phospholipase A2Secreted phospholipase A2-IIA (sPLA2-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA2-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA2-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA2-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA2-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA2-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA2-IIA. In conclusion, sPLA2-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects.MDPIRepositório Científico do Instituto Politécnico de Castelo BrancoMartin, RubenGutierrez, BeatrizMarcos, Cláudia CórdovaSan Roman, AlbertoAlvarez, YolandaHernandez, MaritaCachofeiro, VictoriaNieto, Maria L2020-12-02T10:41:36Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.11/7315engMartin R, Gutierrez B, Cordova C, Roman AS, Alvarez Y, Hernandez M, Cachofeiro V, Nieto ML. Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation-Fibrosis Link. Cells. 2020 Feb 8;9(2):396. doi: 10.3390/cells9020396. PMID: 32046347; PMCID: PMC7072256.10.3390/cells902039632046347info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-01-16T11:47:49Zoai:repositorio.ipcb.pt:10400.11/7315Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T16:37:53.827853Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link |
title |
Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link |
spellingShingle |
Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link Martin, Ruben Cardiac fibroblast Epidermal growth factor receptor Fibrosis Lysyl oxidase Myocarditis Secreted phospholipase A2 |
title_short |
Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link |
title_full |
Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link |
title_fullStr |
Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link |
title_full_unstemmed |
Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link |
title_sort |
Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link |
author |
Martin, Ruben |
author_facet |
Martin, Ruben Gutierrez, Beatriz Marcos, Cláudia Córdova San Roman, Alberto Alvarez, Yolanda Hernandez, Marita Cachofeiro, Victoria Nieto, Maria L |
author_role |
author |
author2 |
Gutierrez, Beatriz Marcos, Cláudia Córdova San Roman, Alberto Alvarez, Yolanda Hernandez, Marita Cachofeiro, Victoria Nieto, Maria L |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Politécnico de Castelo Branco |
dc.contributor.author.fl_str_mv |
Martin, Ruben Gutierrez, Beatriz Marcos, Cláudia Córdova San Roman, Alberto Alvarez, Yolanda Hernandez, Marita Cachofeiro, Victoria Nieto, Maria L |
dc.subject.por.fl_str_mv |
Cardiac fibroblast Epidermal growth factor receptor Fibrosis Lysyl oxidase Myocarditis Secreted phospholipase A2 |
topic |
Cardiac fibroblast Epidermal growth factor receptor Fibrosis Lysyl oxidase Myocarditis Secreted phospholipase A2 |
description |
Secreted phospholipase A2-IIA (sPLA2-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA2-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA2-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA2-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA2-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA2-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA2-IIA. In conclusion, sPLA2-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-12-02T10:41:36Z 2020 2020-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.11/7315 |
url |
http://hdl.handle.net/10400.11/7315 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Martin R, Gutierrez B, Cordova C, Roman AS, Alvarez Y, Hernandez M, Cachofeiro V, Nieto ML. Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation-Fibrosis Link. Cells. 2020 Feb 8;9(2):396. doi: 10.3390/cells9020396. PMID: 32046347; PMCID: PMC7072256. 10.3390/cells9020396 32046347 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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