Secreted Phospholipase A<sub>2</sub>-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link
Secreted phospholipase A<sub>2</sub>-IIA (sPLA<sub>2</sub>-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 sPLA<sub>2...
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MDPI AG
2020-02-01
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| author | Ruben Martin Beatriz Gutierrez Claudia Cordova Alberto San Roman Yolanda Alvarez Marita Hernandez Victoria Cachofeiro Maria L Nieto |
| author_facet | Ruben Martin Beatriz Gutierrez Claudia Cordova Alberto San Roman Yolanda Alvarez Marita Hernandez Victoria Cachofeiro Maria L Nieto |
| author_sort | Ruben Martin |
| collection | DOAJ |
| description | Secreted phospholipase A<sub>2</sub>-IIA (sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA<sub>2</sub>-IIA. In conclusion, sPLA<sub>2</sub>-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. |
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| spelling | doaj.art-a387d70a2d4740c4a41aa73170cb3a732023-09-02T23:24:50ZengMDPI AGCells2073-44092020-02-019239610.3390/cells9020396cells9020396Secreted Phospholipase A<sub>2</sub>-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis LinkRuben Martin0Beatriz Gutierrez1Claudia Cordova2Alberto San Roman3Yolanda Alvarez4Marita Hernandez5Victoria Cachofeiro6Maria L Nieto7Instituto de Ciencias del Corazón, Hospital Clínico Universitario, 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, SpainInstituto de Ciencias del Corazón, Hospital Clínico Universitario, 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, SpainCIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, - 28029 Madrid, SpainInstituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, SpainSecreted phospholipase A<sub>2</sub>-IIA (sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA<sub>2</sub>-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 sPLA<sub>2</sub>-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA<sub>2</sub>-IIA. In conclusion, sPLA<sub>2</sub>-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.https://www.mdpi.com/2073-4409/9/2/396cardiac fibroblastepidermal growth factor receptorlysyl oxidasefibrosismyocarditissecreted phospholipase a<sub>2</sub> |
| spellingShingle | Ruben Martin Beatriz Gutierrez Claudia Cordova Alberto San Roman Yolanda Alvarez Marita Hernandez Victoria Cachofeiro Maria L Nieto Secreted Phospholipase A<sub>2</sub>-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link Cells cardiac fibroblast epidermal growth factor receptor lysyl oxidase fibrosis myocarditis secreted phospholipase a<sub>2</sub> |
| title | Secreted Phospholipase A<sub>2</sub>-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link |
| title_full | Secreted Phospholipase A<sub>2</sub>-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link |
| title_fullStr | Secreted Phospholipase A<sub>2</sub>-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link |
| title_full_unstemmed | Secreted Phospholipase A<sub>2</sub>-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link |
| title_short | Secreted Phospholipase A<sub>2</sub>-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link |
| title_sort | secreted phospholipase a sub 2 sub iia modulates transdifferentiation of cardiac fibroblast through egfr transactivation an inflammation fibrosis link |
| topic | cardiac fibroblast epidermal growth factor receptor lysyl oxidase fibrosis myocarditis secreted phospholipase a<sub>2</sub> |
| url | https://www.mdpi.com/2073-4409/9/2/396 |
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