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

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.

• Authors: N Marui, M K Offermann, R Swerlick, C Kunsch, C A Rosen, M Ahmad, R W Alexander, R M Medford
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 92 Issue 4 Pg. 1866-74 (Oct 1993) ISSN: 0021-9738 [Print] United States
• PMID: 7691889 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antioxidants
• Cell Adhesion Molecules
• DNA Probes
• E-Selectin
• Interleukin-1
• NF-kappa B
• Oligodeoxyribonucleotides
• RNA, Messenger
• Recombinant Proteins
• Tumor Necrosis Factor-alpha
• Vascular Cell Adhesion Molecule-1
• Intercellular Adhesion Molecule-1
• Glyceraldehyde-3-Phosphate Dehydrogenases

Topics

• 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, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression (drug effects)
• Gene Expression Regulation (drug effects, physiology)
• Glyceraldehyde-3-Phosphate Dehydrogenases (biosynthesis)
• Humans
• Intercellular Adhesion Molecule-1
• Interleukin-1 (pharmacology)
• Molecular Sequence Data
• NF-kappa B (metabolism)
• Oligodeoxyribonucleotides (chemical synthesis, metabolism)
• Promoter Regions, Genetic
• RNA, Messenger (drug effects, metabolism)
• Recombinant Proteins (pharmacology)
• Transcription, Genetic (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)
• Umbilical Veins
• Vascular Cell Adhesion Molecule-1