Summary
Activated endothelial cells up-regulate the expression of several molecules on their
plasma membranes, including intercellular adhesion molecule-1 (ICAM-1). The role of
heparin in regulating endothelial cell gene expression is unclear. We thus have investigated
the ability of heparin to regulate ICAM-1 gene expression by using flow cytometry
and the ribonuclease protection assay with human umbilical vein and aortic endothelial
cells cultured in growth medium supplemented with 90 μg/ml heparin (heparin-sufficient,
HS) or in growth medium without added heparin (heparin-deficient, HD). We found that
HD medium increased plasma membrane protein and mRNA for ICAM-1 but not for HLA-DR,
even though both ICAM-1 and HLA-DR protein and mRNA were inducible by gamma interferon
(IFN-γ). In addition, phorbol ester and IFN-γ increased the expression of plasma membrane
ICAM-1 or ICAM-1 and HLA-DR, respectively, more in HD medium than in HS medium. We
found that the HD-mediated increase of ICAM-1 mRNA was reversible by the addition
of heparin, and that the half-life of ICAM-1 mRNA was the same in both HS- and HD-treated
cells. Also, heparin was found to suppress increases in ICAM-1 mRNA at a concentration
as low as 5 μg/ml. These findings indicate that heparin deficiency induces endothelial
activation characterized by increased ICAM-1, and that such induction is not dependent
on cytokines or endotoxin. The modulation of ICAM-1 expression by heparin appears
to occur at the transcriptional level. Thus, heparin may have a role in regulating
endothelial function by affecting the expression of ICAM-1, thereby impacting upon
the trans-endothelial trafficking of leukocytes.
