title: Critical role of hydrogen peroxide signaling in the sequential activation of p38 MAPK and eNOS in laminar shear stress.
abstract: Laminar shear stress (LSS) is a protective hemodynamic regulator of endothelial function and limits the development of atherosclerosis and other vascular wall diseases related to pathophysiological generation of reactive oxygen species. LSS activates several endothelial signaling responses, including the activation of MAPKs and eNOS. Here, we explored the mechanisms of activation of these key endothelial signaling pathways. Using the cone/plate model we found that LSS (12 dyn/cm(2)) rapidly promotes endothelial intracellular generation of superoxide and hydrogen peroxide (H(2)O(2)). Physiological concentrations of H(2)O(2) (flux of 0.1 nM/min and 15 μM added extracellularly) significantly activated both eNOS and p38 MAPK. Pharmacological inhibition of NADPH oxidases (NOXs) and specific knockdown of NOX4 decreased LSS-induced p38 MAPK activation. Whereas the absence of eNOS did not alter LSS-induced p38 MAPK activation, pharmacological inhibition and knockdown of p38α MAPK blocked H(2)O(2)- and LSS-induced eNOS phosphorylation and reduced (•)NO levels. We propose a model in which LSS promotes the formation of signaling levels of H(2)O(2), which in turn activate p38α MAPK and then stimulate eNOS, leading to increased (•)NO generation and protection of endothelial function.
authors.affiliation: Laboratorio Mixto CSIC-FRIAT de Fisiopatología Vascular y Renal, Centro de Biología Molecular Severo Ochoa, Campus Universidad Autónoma, 28049 Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bretón-Romero
authors.forename: Cecilia
authors.initials: C
authors.lastname: González de Orduña
authors.forename: Natalia
authors.initials: N
authors.lastname: Romero
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Sánchez-Gómez
authors.forename: Cristina
authors.initials: C
authors.lastname: de Álvaro
authors.forename: Almudena
authors.initials: A
authors.lastname: Porras
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-Pascual
authors.forename: Joao
authors.initials: J
authors.lastname: Laranjinha
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
authors.forename: Santiago
authors.initials: S
authors.lastname: Lamas
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012039:Regional Blood Flow; D033081:Shear Strength; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048051:p38 Mitogen-Activated Protein Kinases