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Open AccessArticle

Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

1
Instituto de Ciencias del Corazón, Hospital Clínico Universitario, 47003 Valladolid, Spain
2
Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain
3
Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Spain. Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28040 Madrid, Spain
4
CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, - 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Present Address: Escola Superior de Saúde Dr. Lopes Dias, Instituto Politécnico de Castelo Branco, 6000-767 Castelo Branco, Portugal.
Cells 2020, 9(2), 396; https://doi.org/10.3390/cells9020396
Received: 23 December 2019 / Revised: 29 January 2020 / Accepted: 3 February 2020 / Published: 8 February 2020
(This article belongs to the Special Issue Cells in Cardiovascular Disease)
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.
Keywords: cardiac fibroblast; epidermal growth factor receptor; lysyl oxidase; fibrosis; myocarditis; secreted phospholipase A2 cardiac fibroblast; epidermal growth factor receptor; lysyl oxidase; fibrosis; myocarditis; secreted phospholipase A2
MDPI and ACS Style

Martin, R.; Gutierrez, B.; Cordova, C.; Roman, A.S.; Alvarez, Y.; Hernandez, M.; Cachofeiro, V.; Nieto, M.L. Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link. Cells 2020, 9, 396.

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