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 pa thogenesis of atherosclerosis and other inflammatory diseases. Regulat ion of VCAM-1 gene expression may be coupled to oxidative stress throu gh specific reduction-oxidation(redox) sensitive transcriptional or po sttranscriptional regulatory factors. In cultured human umbilical vein endothelial (HUVE) cells, the cytokine interleukin 1beta (IL-1beta) a ctivated VCAM-1 gene expression through a mechanism that was repressed approximately 90% by the antioxidants pyrrolidine dithiocarbamate (PD TC) and N-acetylcysteine (NAC). Furthermore, PDTC selectively inhibite d 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 endotoxi n lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). P DTC also markedly attenuated TNFalpha induction of VCAM-1-mediated cel lular adhesion. In a distinct pattern, PDTC partially inhibited E-sele ctin gene expression in response to TNFalpha but not to LPS, IL-1beta, or PIC. TNFalpha and LPS-mediated transcriptional activation of the h uman 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 sensi tive transcriptional regulatory mechanism and VCAM-I gene expression t hat expands on the notion of oxidative stress as an important regulato ry signal in the pathogenesis of atherosclerosis.