RT info:eu-repo/semantics/article
T1 Secreted phospholipase A2-IIA modulates transdifferentiation of cardiac fibroblast through EGFR transactivation: An inflammation–fibrosis link
A1 Martín, Rubén
A1 Gutiérrez, Beatriz
A1 Córdova, Claudia
A1 San Román, Alberto
A1 Alvarez, Yolanda
A1 Hernández Garrido, Marita
A1 Cachofeiro, Victoria
A1 Nieto, Maria Luisa
K1 Cardiac fibroblasts
K1 Fibroblastos cardiacos
K1 Lysyl oxidase
K1 Lisil oxidasa
K1 Fibrosis
K1 Myocarditis
K1 Miocarditis
AB 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.
PB MDPI
SN 2073-4409
YR 2020
FD 2020
LK https://uvadoc.uva.es/handle/10324/52601
UL https://uvadoc.uva.es/handle/10324/52601
LA eng
NO Cells, 2020, vol. 9, n. 2, 396
NO Producción Científica
DS UVaDOC
RD 17-jul-2024