Vascular smooth muscle cell (VSMC) hyperplasia plays a central role in chronic and acute vascular pathology including arteriosclerosis and restenosis following vascular surgery. The glycosaminoglycans of the heparan sulfate class, including heparin, inhibit VSMC proliferation in animals and in culture. Heparin binds to high affinity sites on the cell surface, selectively modulates mitogenic signal transduction pathway(s), and rapidly alters transcription of several genes. To further explore the molecular mechanisms responsible for this growth inhibition, we have employed the differential display technique to identify heparin-regulated genes. Here we demonstrate that heparin inhibits the expression of the early response gene sgk (serum and glucocorticoid-regulated kinase). The expression of sgk is not inhibited by chondroitin sulfate, a nonantiproliferative glycosaminoglycan, suggesting that sgk suppression may play a functional role in the antiproliferative effect of heparin. This idea is strengthened by the finding that heparin does not inhibit sgk expression in VSMCs resistant to the antiproliferative effect of heparin or in vascular endothelial cells which are unresponsive to heparin. Expression of sgk mRNA diminishes with increasing concentrations of heparin. Finally, sgk expression is not suppressed by other growth inhibitors such as transforming growth factor-beta 1 (TGF-beta 1) and interferon-beta (IFN-beta), suggesting separate and distinct effects of these growth inhibitors on the mitogenic pathway.