Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells.
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.
Marui
N
N
Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia 30322.
Offermann
M K
MK
Swerlick
R
R
Kunsch
C
C
Rosen
C A
CA
Ahmad
M
M
Alexander
R W
RW
Medford
R M
RM
D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015342:DNA Probes; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1; D007375:Interleukin-1 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1
D000975:Antioxidants; D015815:Cell Adhesion Molecules; D015342:DNA Probes; D019040:E-Selectin; D007375:Interleukin-1; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases