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Secreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis link

2020Journal article Open access
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dc.contributor.authorMartin, Ruben
dc.contributor.authorGutierrez, Beatriz
dc.contributor.authorMarcos, Cláudia Córdova
dc.contributor.authorSan Roman, Alberto
dc.contributor.authorAlvarez, Yolanda
dc.contributor.authorHernandez, Marita
dc.contributor.authorCachofeiro, Victoria
dc.contributor.authorNieto, Maria L.
dc.date.accessioned2020-12-02T10:41:36Z
dc.date.available2020-12-02T10:41:36Z
dc.date.issued2020
dc.description.abstractSecreted 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMartin 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.pt_PT
dc.identifier.doi10.3390/cells9020396pt_PT
dc.identifier.pmid32046347
dc.identifier.urihttp://hdl.handle.net/10400.11/7315
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relation.publisherversionhttps://www.mdpi.com/2073-4409/9/2/396pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectCardiac fibroblastpt_PT
dc.subjectEpidermal growth factor receptorpt_PT
dc.subjectFibrosispt_PT
dc.subjectLysyl oxidasept_PT
dc.subjectMyocarditispt_PT
dc.subjectSecreted phospholipase A2pt_PT
dc.titleSecreted phospholipase A 2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: an inflammation-fibrosis linkpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.titleCellspt_PT
person.familyNameC´órdova Marcos
person.givenNameCláudia
person.identifier.ciencia-id8014-8F33-74AF
person.identifier.orcid0000-0002-2108-2629
person.identifier.scopus-author-id55259775600
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication7241ff3f-7c4f-4688-b938-5dae4ca343dd
relation.isAuthorOfPublication.latestForDiscovery7241ff3f-7c4f-4688-b938-5dae4ca343dd

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