title: Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway.
abstract: During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-κB pathway. Oxidative stress induces the expression and secretion of TGF-β1 and TGF-β2 and p38 MAPK phosphorylation. Downregulation of TGF-β1 and TGF-β2 by siRNA technology abolished the H2O2-induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-β secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-β-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.
authors: Laboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors: Ignacio
authors: I
authors: Montorfano
authors: Laboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors: Alvaro
authors: A
authors: Becerra
authors: Laboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors: Roberto
authors: R
authors: Cerro
authors: 1] Laboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile [2] Laboratorio de Bionanotecnología, Universidad Bernardo O'Higgins, Santiago, Chile.
authors: César
authors: C
authors: Echeverría
authors: Laboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors: Elizabeth
authors: E
authors: Sáez
authors: Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors: María Gabriela
authors: MG
authors: Morales
authors: Laboratorio de Fisiología, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors: Ricardo
authors: R
authors: Fernández
authors: Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile.
authors: Claudio
authors: C
authors: Cabello-Verrugio
authors: 1] Laboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas and Facultad de Medicina, Universidad Andres Bello, Santiago, Chile [2] Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
authors: Felipe
authors: F
authors: Simon
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016326:Extracellular Matrix Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human