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 1beta (IL-1beta) 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 (TNFalpha) as well as the noncytokines bacterial endotoxin lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). PDTC also markedly attenuated TNFalpha induction of VCAM-1-mediated cellular adhesion. In a distinct pattern, PDTC partially inhibited E-selectin gene expression in response to TNFalpha but not to LPS, IL-1beta, or PIC. TNFalpha and LPS-mediated transcriptional activation of the human VCAM-1 promoter through NF-kappaB-like DNA enhancer elements and associated NF-kappaB-like DNA binding proteins was inhibited by PDTC. These studies suggest a molecular linkage between an antioxidant sensitive transcriptional regulatory mechanism and VCAM-I gene expression that expands on the notion of oxidative stress as an important regulatory signal in the pathogenesis of atherosclerosis.