NF-kappa B is activated and ICAM-1 gene expression is upregulated during reoxygenation of human brain endothelial cells.
Reperfusion injury is mediated, in part, by the upregulated expression of genes in microvascular endothelial cells that encode for inflammatory cytokines and adhesion molecules. The redox-regulated transcription factor, nuclear factor kappa B (NF-kappaB), may play a major role in the induced expression of these genes. In this study we use cultured human brain microvascular endothelial cells (HBMEC) to investigate whether reoxygenation of hypoxic HBMEC results in the activation of NF-kappaB and the upregulation of the adhesion molecule, ICAM-1. When HBMEC were subjected to hypoxia followed by reoxygenation but not hypoxia alone, an NF-kappaB complex composed of p65 and p50 Rel proteins was rapidly activated within 15-30 min. Four hours later, expression of the ICAM-1 gene was significantly upregulated. The antioxidant pyrrolidine dithiocarbamate and the proteasome inhibitor, n-Tosyl-Phe-chloromethyl ketone, blocked both the activation of NF-kappaB and the upregulation of the ICAM-1 gene. These results indicate that NF-kappaB is activated in HBMEC by reoxygenation and may play a significant role in the upregulation of the ICAM-1 gene. Agents which inhibit NF-kappaB activation may be potential therapeutic agents in acute ischemic stroke.
Howard
E F
EF
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, USA.
Chen
Q
Q
Cheng
C
C
Carroll
J E
JE
Hess
D
D
D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1