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      Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells.

      The Journal of clinical investigation

      Antioxidants, pharmacology, Base Sequence, Binding Sites, Blotting, Northern, Cell Adhesion Molecules, analysis, biosynthesis, genetics, Cell Nucleus, metabolism, Cells, Cultured, DNA Probes, E-Selectin, Endothelium, Vascular, drug effects, Enzyme-Linked Immunosorbent Assay, Gene Expression, Gene Expression Regulation, physiology, Glyceraldehyde-3-Phosphate Dehydrogenases, Humans, Intercellular Adhesion Molecule-1, Interleukin-1, Molecular Sequence Data, NF-kappa B, Oligodeoxyribonucleotides, chemical synthesis, Promoter Regions, Genetic, RNA, Messenger, Recombinant Proteins, Transcription, Genetic, Tumor Necrosis Factor-alpha, Umbilical Veins, Vascular Cell Adhesion Molecule-1

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          Abstract

          Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. Regulation of VCAM-1 gene expression may be coupled to oxidative stress through specific reduction-oxidation (redox) sensitive transcriptional or posttranscriptional regulatory factors. In cultured human umbilical vein endothelial (HUVE) cells, the cytokine interleukin 1 beta (IL-1 beta) activated VCAM-1 gene expression through a mechanism that was repressed approximately 90% by the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC). Furthermore, PDTC selectively inhibited the induction of VCAM-1, but not intercellular adhesion molecule-1 (ICAM-1), mRNA and protein accumulation by the cytokine tumor necrosis factor-alpha (TNF alpha) as well as the noncytokines bacterial endotoxin lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). PDTC also markedly attenuated TNF alpha induction of VCAM-1-mediated cellular adhesion. In a distinct pattern, PDTC partially inhibited E-selectin gene expression in response to TNF alpha but not to LPS, IL-1 beta, or PIC. TNF alpha and LPS-mediated transcriptional activation of the human VCAM-1 promoter through NF-kappa B-like DNA enhancer elements and associated NF-kappa B-like DNA binding proteins was inhibited by PDTC. These studies suggest a molecular linkage between an antioxidant sensitive transcriptional regulatory mechanism and VCAM-1 gene expression that expands on the notion of oxidative stress as an important regulatory signal in the pathogenesis of atherosclerosis.

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          Journal
          7691889
          288351
          10.1172/JCI116778

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