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      Lactosylceramide Mediates Shear-Induced Endothelial Superoxide Production and Intercellular Adhesion Molecule-1 Expression

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          Laminar shear stress activates NADPH oxidase in vascular endothelial cells (ECs), and the generated superoxide radicals (O<sub>2</sub><sup>–</sup>·) are known to be involved in intercellular adhesion molecule (ICAM)-1 expression. In this study, the role of a glycosphingolipid (GSL), lactosylceramide (LacCer), as a second messenger in the shear-induced O<sub>2</sub><sup>–</sup>· generation and ICAM-1 expression was examined. It is known that glucosylceramide synthase (GlcT-1) catalyzes the synthesis of glucosylceramide (GlcCer) from ceramide, and subsequently lactosylceramide synthase (GalT-2) synthesizes LacCer from GlcCer. We observed that exposing cultured human umbilical vein ECs (HUVECs) to fluid shear stress (20 dyn/cm<sup>2</sup> for 30 min) activated GalT-2. Shear stress also increased EC O<sub>2</sub><sup>–</sup>· generation, that peaked at 30 min, and surface ICAM-1 protein expression at 6 h post-shear. EC preincubation with the antioxidant N-acetylcysteine (NAC; 20 m M for 2 h) completely abolished the shear-induced O<sub>2</sub><sup>–</sup>· production and significantly inhibited ICAM-1 expression. EC preincubation with D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol ( D-PDMP), an inhibitor of the GSL glycosyltransferases GlcT-1 and GalT-2, abrogated the shear-induced activation of GalT-2. D-PDMP also abolished the shear-induced O<sub>2</sub><sup>–</sup>· production and ICAM-1 expression. We conclude that laminar shear stress activates GalT-2 to produce LacCer. In turn, LacCer activates NADPH oxidase, which produces O<sub>2</sub><sup>–</sup>·, and O<sub>2</sub><sup>–</sup>· mediates the shear-induced increase in ICAM-1 expression. Thus, LacCer may play an important role in hemodynamic force-induced pathological conditions, such as atherosclerosis and ischemia/reperfusion injury.

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          Most cited references 7

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          Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1.

          Professional phagocytes, such as neutrophils and monocytes, have an NADPH oxidase that generates superoxide and other reduced oxygen species important in killing microorganisms. Several components of the oxidase complex have been identified as targets of genetic defects causing chronic granulomatous disease. The complex consists of an electron transport chain that has as its substrate cytosolic NADPH and which discharges superoxide into the cavity of the intracellular phagocytic vacuole. The only electron transport component identified so far is a low-potential cytochrome b, apparently the only membrane component required. At least three cytosolic factors are also necessary, two of which, p67phOx and p47phOx, have been identified by their absence in patients with chronic granulomatous disease. A third component, sigma 1, is required for stimulation of oxidase activity in a cell-free system. The active components of purified sigma 1 are two proteins that associate as heterodimers, and here we report that these are the small GTP-binding protein p21rac1 and the GDP-dissociation inhibitor rhoGDI.
            • Record: found
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            Tumor necrosis factor-  induces adhesion molecule expression through the sphingosine kinase pathway

             M Vadas,  P Xia,  J R Gamble (1998)
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              Fluid Shear Stress Activation of Focal Adhesion Kinase


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2001
                07 December 2001
                : 38
                : 6
                : 551-559
                aVascular Bioengineering Laboratory, Department of Biomedical Engineering and bLipid Research Atherosclerosis Unit, Department of Pediatrics of the Johns Hopkins University School of Medicine, Baltimore, Md., USA
                51091 J Vasc Res 2001;38:551–559
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 45, Pages: 9
                Research Paper


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