Martin, RubenGutierrez, BeatrizMarcos, Cláudia CórdovaSan Roman, AlbertoAlvarez, YolandaHernandez, MaritaCachofeiro, VictoriaNieto, Maria L.2020-12-022020-12-022020Martin 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.http://hdl.handle.net/10400.11/7315Secreted 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.engCardiac fibroblastEpidermal growth factor receptorFibrosisLysyl oxidaseMyocarditisSecreted phospholipase A2journal article10.3390/cells902039632046347