title: Increases in reactive oxygen species enhance vascular endothelial cell migration through a mechanism dependent on the transient receptor potential melastatin 4 ion channel.
abstract: A hallmark of severe inflammation is reactive oxygen species (ROS) overproduction induced by increased inflammatory mediators secretion. During systemic inflammation, inflammation mediators circulating in the bloodstream interact with endothelial cells (ECs) raising intracellular oxidative stress at the endothelial monolayer. Oxidative stress mediates several pathological functions, including an exacerbated EC migration. Because cell migration critically depends on calcium channel-mediated Ca(2+) influx, the molecular identification of the calcium channel involved in oxidative stress-modulated EC migration has been the subject of intense investigation. The transient receptor potential melastatin 4 (TRPM4) protein is a ROS-modulated non-selective cationic channel that performs several cell functions, including regulating intracellular Ca(2+) overload and Ca(2+) oscillation. This channel is expressed in multiple tissues, including ECs, and contributes to the migration of certain immune cells. However, whether the TRPM4 ion channel participates in oxidative stress-mediated EC migration is not known. Herein, we investigate whether oxidative stress initiates or enhances EC migration and study the role played by the ROS-modulated TRPM4 ion channel in oxidative stress-mediated EC migration. We demonstrate that oxidative stress enhances, but does not initiate, EC migration in a dose-dependent manner. Notably, we demonstrate that the TRPM4 ion channel is critical in promoting H2O2-enhanced EC migration. These results show that TRPM4 is a novel pharmacological target for the possible treatment of severe inflammation and other oxidative stress-mediated inflammatory diseases.
authors: Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile.
authors: Daniela
authors: D
authors: Sarmiento
authors: Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile.
authors: Ignacio
authors: I
authors: Montorfano
authors: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Oscar
authors: O
authors: Cerda
authors: Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Mónica
authors: M
authors: Cáceres
authors: Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile.
authors: Alvaro
authors: A
authors: Becerra
authors: Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile.
authors: Claudio
authors: C
authors: Cabello-Verrugio
authors: Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
authors: Alvaro A
authors: AA
authors: Elorza
authors: Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
authors: Claudia
authors: C
authors: Riedel
authors: Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Pablo
authors: P
authors: Tapia
authors: Center for Integrative Medicine and Innovative Science (CIMIS), Facultad de Medicina, Universidad Andres Bello, Santiago, Chile; Centro para el Desarrollo de la Nanociencia y Nanotecnología, Universidad de Santiago de Chile, Santiago, Chile.
authors: Luis A
authors: LA
authors: Velásquez
authors: Programa de Fisiopatología, Centro de Estudios Moleculares de la Célula and Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors: Diego
authors: D
authors: Varela
authors: Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Santiago, Chile. Electronic address: fsimon@unab.cl.
authors: Felipe
authors: F
authors: Simon
mesh_terms: D002448:Cell Adhesion; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007249:Inflammation / Q000378:metabolism; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human; D006861:Hydrogen Peroxide