期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 89, 期 -, 页码 419-430出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.08.014
关键词
Endothelium; Laminar shear stress; Hydrogen peroxide; Sulfenylation; Redox signaling; Vasodilation; Free radicals
资金
- Ministerio de Economia y Competitividad [SAF 2012-31338, CSD 2007-00020, SAF 2010-37926]
- Institut de Salud Carlos III [REDinREN RD12/0021/0009, ProteoRed-PT13/0001/0017, RETIC-RD12/0042/0056]
- Deutsche Forschungsgemeinschaft [SFB815/TP1, SCHR1241/1-1]
- German Center for Cardiovascular Research
- Comunidad de Madrid Fibroteam [52010/BMD-2321]
- Fundacion Renal Inigo Alvarez de Toledo
- European Cooperation in Science and Technology actions [BM-1203, BM-1005]
- British Heart Foundation
- British Heart Foundation [RG/13/11/30384] Funding Source: researchfish
Laminar shear stress (LSS) triggers signals that ultimately result in atheroprotection and vasodilatation. Early responses are related to the activation of specific signaling cascades. We investigated the participation of redox-mediated modifications and in particular the role of hydrogen peroxide (H2O2) in the sulfenylation of redox-sensitive phosphatases. Exposure of vascular endothelial cells to short periods of LSS (12 dyn/cm(2)) resulted in the generation of superoxide radical anion as detected by the formation of 2-hydroxyethidium by HPLC and its subsequent conversion to H2O2, which was corroborated by the increase in the fluorescence of the specific peroxide sensor Hyper. By using biotinylated dimedone we detected increased total protein sulfenylation in the bovine proteome, which was dependent on NADPH oxidase 4 (NOX4)-mediated generation of peroxide. Mass spectrometry analysis allowed us to identify the phosphatase SHP2 as a protein susceptible to sulfenylation under LSS. Given the dependence of FAK activity on SHP2 function, we explored the role of FAK under LSS conditions. FAK activation and subsequent endothelial NO synthase (eNOS) phosphorylation were promoted by LSS and both processes were dependent on NOX4, as demonstrated in lung endothelial cells isolated from NOX4-null mice. These results support the idea that LSS elicits redox-sensitive signal transduction responses involving NOX4-dependent generation of hydrogen peroxide, SHP2 sulfenylation, and ulterior FAK-mediated eNOS activation. (C) 2015 Elsevier Inc. All rights reserved.
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