Critical role of hydrogen peroxide signaling in the sequential activation of p38 MAPK and eNOS in laminar shear stress

被引:63
作者
Breton-Romero, Rosa [1 ]
Gonzalez de Orduna, Cecilia [1 ]
Romero, Natalia [2 ,3 ]
Sanchez-Gomez, Francisco J. [1 ]
de Alvaro, Cristina [1 ]
Porras, Almudena [4 ]
Rodriguez-Pascual, Fernando [1 ]
Laranjinha, Joao [5 ]
Radi, Rafael [2 ,3 ]
Lamas, Santiago [1 ]
机构
[1] Ctr Biol Mol Severo Ochoa, Lab Mixto CSIC FRIAT Fisiopatol Vasc & Renal, Madrid 28049, Spain
[2] Univ Republica, Fac Med, Dept Bioquim, Montevideo, Uruguay
[3] Univ Republica, Fac Med, Ctr Free Radical & Biomed Res, Montevideo, Uruguay
[4] UCM, Fac Farm, Dept Bioquim & Biol Mol 2, Madrid 28040, Spain
[5] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal
关键词
Laminar shear stress; Hydrogen peroxide; Endothelial nitric oxide; p38; MAPK; NADPH oxidase; Free radicals; NITRIC-OXIDE SYNTHASE; VASCULAR ENDOTHELIAL-CELLS; AKT-DEPENDENT PHOSPHORYLATION; NADPH OXIDASE; PROTEIN-KINASE; IN-VIVO; EXPRESSION; H2O2; PATHWAY; NOX4;
D O I
10.1016/j.freeradbiomed.2011.12.026
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
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 (H2O2). Physiological concentrations of H2O2 (flux of 0.1 nM/min and 151. mu M 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 p38 alpha. MAPK blocked H2O2- and LSS-induced eNOS phosphorylation and reduced NO levels. We propose a model in which LSS promotes the formation of signaling levels of H2O2, which in turn activate p38 alpha MAPK and then stimulate eNOS, leading to increased NO generation and protection of endothelial function. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:1093 / 1100
页数:8
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