Endothelial Activation Following Prolonged Hypobaric Hypoxia
Department of Neurology, University of Arkansas School of Medicine, Little Rock, Arkansas Microvascular Research
(Impact Factor: 2.13).
04/1999; 57(2):75-85. DOI: 10.1006/mvre.1998.2112
Prolonged exposure to low oxygen may induce adaptive changes which can be either beneficial or deleterious to cell survival. We examined the effect of prolonged moderate hypobaric hypoxia on CNS endothelial cell (EC) function. Exposure to hypoxia resulted in expression of EC activation markers, the cell surface adhesion proteins intracellular adhesion molecule-1 and E-selectin. Induction of the major histocompatibility complex (MHC) class II molecule as well as increased constitutive expression of the transferrin receptor and the glucose transporter-1 protein was also detected within 24 h of exposure to hypobaric hypoxia. Constitutive expression of the MHC class I molecule increased by 48 h. Expression of most EC activation markers increased with time from 0 to 2 weeks. By 3 weeks of exposure to hypobaric hypoxia, ECs returned to their quiescent state with the exception of sustained expression of E-selectin and elevated glut-1. Little to no significant increase in expression of vascular cell adhesion molecule-1 was seen at any time period.
Available from: Gregory L Stahl
- "MBL is a C-type lectin whose binding is calciumdependent and has a high specificity to N-acetyl-D-glucosamine (GlcNAc), mannose or their oligomers (Thiel et al. 1997). Although the molecular mechanism by which oxidative stress increases MBL binding to endothelial cells is at present unclear, hypoxia alters endothelial protein synthesis and surface expression (Ogawa et al. 1991; Weinhouse et al. 1993; Dore-Duffy et al. 1999). Other lectins derived from plant sources have binding profiles similar to that of MBL. "
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ABSTRACT: Complement is an important mediator of vascular injury following oxidative stress. We recently demonstrated that complement activation following endothelial oxidative stress is mediated by mannose-binding lectin (MBL) and activation of the lectin complement pathway. Here, we investigated whether nine plant lectins which have a binding profile similar to that of MBL competitively inhibit MBL deposition and subsequent complement activation following human umbilical vein endothelial cell (HUVEC) oxidative stress. HUVEC oxidative stress (1% O(2), 24 hr) significantly increased Ulex europaeus agglutinin II (UEA-II) binding by 72 +/- 9% compared to normoxic cells. UEA-II inhibited MBL binding to HUVEC in a concentration-dependent manner following oxidative stress. Further, MBL inhibited UEA-II binding to HUVEC in a concentration-dependent manner following oxidative stress, suggesting a common ligand. UEA-II (< or = 100 micromol/L) did not attenuate the hemolytic activity, nor did it inhibit C3a des Arg formation from alternative or classical complement pathway-specific hemolytic assays. C3 deposition (measured by ELISA) following HUVEC oxidative stress was inhibited by UEA-II in a concentration-dependent manner (IC(50) = 10 pmol/L). UEA-II inhibited C3 and MBL co-localization (confocal microscopy) in a concentration-dependent manner on HUVEC following oxidative stress (IC(50) approximately 1 pmol/L). Finally, UEA-II significantly inhibited complement-dependent neutrophil chemotaxis, but failed to inhibit fMLP-mediated chemotaxis, following endothelial oxidative stress. These data demonstrate that UEA-II is a novel, potent inhibitor of human MBL deposition and complement activation following human endothelial oxidative stress.
Available from: jimmunol.org
Available from: Prem Ponka
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ABSTRACT: Expression of the transferrin receptor, which mediates iron uptake from transferrin, is negatively regulated post-transcriptionally by intracellular iron through iron-responsive elements in the 3'-untranslated region of the transferrin receptor mRNA. Transcriptional mechanisms are also involved in receptor expression, but these are poorly understood. In this study we have characterized the transferrin receptor promoter region and identified a functional hypoxia response element that contains a binding site for hypoxia-inducible factor-1 (HIF-1). Exposure of K562 and HeLa cells to hypoxia for 16 h resulted in a 2- to 3-fold increase in transferrin receptor mRNA expression. A motif with multipartite organization similar to the hypoxia response element of a number of hypoxia-inducible genes such as erythropoietin was identified within a 100-base pair sequence upstream of the transcriptional start site. Mutation of a site similar to the consensus HIF-binding site (HBS) in this motif attenuated the hypoxic response by 80%. Transient co-expression of the two HIF-1 subunits (HIF-1alpha and HIF-1beta) enhanced the wild type transferrin receptor promoter activity, but that which contained a mutated HBS yielded no such response. Electrophoretic mobility shift assays revealed that HIF-1 was stimulated and bound to the transferrin receptor HBS upon hypoxic challenge. Our results indicate that the transferrin receptor is a target gene for HIF-1.
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