HEPARIN SUPPRESSES SGK, AN EARLY RESPONSE GENE IN PROLIFERATING VASCULAR SMOOTH-MUSCLE CELLS

Vascular smooth muscle cell (VSMC) hyperplasia plays a central role in chronic and acute vascular pathology including arteriosclerosis and r estenosis following vascular surgery. The glycosaminoglycans of the he paran sulfate class, including heparin, inhibit VSMC proliferation in animals and in culture. Heparin binds to high affinity sites on the ce ll surface, selectively modulates mitogenic signal transduction pathwa y(s), and rapidly alters transcription of several genes. To further ex plore the molecular mechanisms responsible for this growth inhibition, we have employed the differential display technique to identify hepar in-regulated genes. Here we demonstrate that heparin inhibits the expr ession of the early response gene sgk (serum and glucocorticoid-regula ted kinase). The expression of sgk is not inhibited by chondroitin sul fate, a nonantiproliferative glycosaminoglycan, suggesting that sgk su ppression may play a functional role in the antiproliferative effect o f 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 unrespon sive to heparin. Expression of sgk mRNA diminishes with increasing con centrations of heparin. Finally, sgk expression is not suppressed by o ther growth inhibitors such as transforming growth factor-beta 1 (TCF- beta 1) and interferon-beta (IFN-beta), suggesting separate and distin ct effects of these growth inhibitors on the mitogenic pathway. (C) 19 97 Wiley-Liss, Inc.