HEPARIN REGULATES ICAM-1 EXPRESSION IN HUMAN ENDOTHELIAL-CELLS - AN EXAMPLE OF NON-CYTOKINE-MEDIATED ENDOTHELIAL ACTIVATION

Activated endothelial cells up-regulate the expression of several mole cules on their plasma membranes, including intercellular adhesion mole cule-1 (ICAM-1). The role of heparin in regulating endothelial cell ge ne expression is unclear. We thus have investigated the ability of hep arin to regulate ICAM-1 gene expression by using flow cytometry and th e ribonuclease protection assay with human umbilical vein and aortic e ndothelial cells cultured in growth medium supplemented with 90 mu g/m l heparin (heparin-sufficient, HS) or in growth medium without added h eparin (heparin-deficient, HD). We found that KD medium in creased pla sma membrane protein and mRNA for ICAM-1 but not for HLA-DR, even thou gh both ICAM-1 and HLA-DR protein and mRNA were inducible by gamma int erferon (IFN-gamma). In addition, phorbol ester and IFN-gamma increase d the expression of plasma membrane ICAM-1 or ICAM-1 and HLA-DR, respe ctively, more in HD medium than in I-IS medium. We found that the HD-m ediated increase of ICAM-1 mRNA was reversible by the addition of hepa rin, and that the half-life of ICAM-1 mRNA was the same in both HS- an d HD-treated cells. Also, heparin was found to suppress increases in I CAM-1 mRNA at a concentration as low as 5 mu g/ml. These findings indi cate that heparin deficiency induces endothelial activation characteri zed by increased ICAM-1, and that such induction is not dependent on c ytokines or endotoxin. The modulation of ICAM-1 expression by heparin appears to occur at the transcriptional level. Thus, heparin map have a role in regulating endothelial function by affecting the expression of ICAM-1, thereby impacting upon the trans-endothelial trafficking of leukocytes.