{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T02:40:41Z","timestamp":1789872041373,"version":"4.0.1"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,8]],"date-time":"2020-02-08T00:00:00Z","timestamp":1581120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010198","name":"MINECO","doi-asserted-by":"publisher","award":["SAF2012-34460 and SAF2016-81063"],"award-info":[{"award-number":["SAF2012-34460 and SAF2016-81063"]}],"id":[{"id":"10.13039\/501100010198","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI18\/010257729"],"award-info":[{"award-number":["PI18\/010257729"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012513","name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Cardiovasculares","doi-asserted-by":"publisher","award":["CIBERCV"],"award-info":[{"award-number":["CIBERCV"]}],"id":[{"id":"10.13039\/501100012513","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells9020396","type":"journal-article","created":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T11:48:51Z","timestamp":1581335331000},"page":"396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation\u2013Fibrosis Link"],"prefix":"10.3390","volume":"9","author":[{"given":"Ruben","family":"Martin","sequence":"first","affiliation":[{"name":"Instituto de Ciencias del Coraz\u00f3n, Hospital Cl\u00ednico Universitario, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Cordova","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"San Roman","sequence":"additional","affiliation":[{"name":"Instituto de Ciencias del Coraz\u00f3n, Hospital Cl\u00ednico Universitario, 47003 Valladolid, Spain"},{"name":"CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, - 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marita","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6959-6293","authenticated-orcid":false,"given":"Victoria","family":"Cachofeiro","sequence":"additional","affiliation":[{"name":"CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, - 28029 Madrid, Spain"},{"name":"Departamento de Fisiolog\u00eda, Facultad de Medicina, Universidad Complutense de Madrid, Spain. Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n (IiSGM), 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6842-799X","authenticated-orcid":false,"given":"Maria L","family":"Nieto","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda y Gen\u00e9tica Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain"},{"name":"CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, - 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/S0140-6736(11)60648-X","article-title":"Myocarditis","volume":"379","author":"Sagar","year":"2012","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0065-2776(08)00604-4","article-title":"Chapter 4 Pathogenesis of myocarditis and dilated cardiomyopathy","volume":"99","author":"Cihakova","year":"2008","journal-title":"Adv. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/3-540-30822-9_9","article-title":"The significance of autoimmunity in myocarditis","volume":"55","author":"Rose","year":"2006","journal-title":"Ernst Scher. Res. Found. 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