GLUCOCORTICOID INHIBITS THROMBIN-INDUCED EXPRESSION OF PLATELET-DERIVED GROWTH-FACTOR A-CHAIN AND HEPARIN-BINDING EPIDERMAL GROWTH FACTOR-LIKE GROWTH-FACTOR IN HUMAN AORTIC SMOOTH-MUSCLE CELLS

Proliferation of smooth muscle cells (SMCs) in atherosclerosis may be modulated by several growth regulatory molecules. At least two mitogen s for SMCs, platelet-derived growth factor (PDGF) A-chain and heparin- binding epidermal growth factor-like growth factor (HB-EGF), can be pr oduced by SMCs themselves and may stimulate smooth muscle proliferatio n in an autocrine or paracrine fashion. We examined the effects of thr ombin, which may be generated at the site of vascular injury during at herogenesis, and the potent anti-inflammatory glucocorticoid, dexameth asone (DEX), on the expression of the genes encoding these two growth factors. Since both PDGF A-chain and HB-EGF have affinity for heparin, we also examined the effect of thrombin and DEX on the release of hep arin binding mitogenic activity from SMCs. Treatment of SMCs with thro mbin resulted in increases both in the level of the PDGF-A and HB-EGF transcripts in the cells, as well as in released heparin-binding growt h factor activity. DEX inhibits the thrombin-stimulated release of mit ogenic activity in a dose-dependent manner. An enzyme-linked immunoads orbent assay showed that DEX inhibits both constitutive and thrombin-s timulated release of PDGF-AA. DEX also decreases both constitutive and thrombin-stimulated mRNA levels for PDGF A-chain and HB-EGF and desta bilizes the transcripts for both growth factors. A nuclear run-on assa y revealed that DEX acts, in addition, to inhibit constitutive and thr ombin-stimulated transcription of the PDGF A-chain and HB-EGF genes. T hus, these findings indicate that expression of PDGF A-chain and HB-EG F may be regulated by thrombin and glucocorticoid at the transcription level. Our results are consistent with the involvement of thrombin-in duced growth factor expression in neointimal SMC proliferation and sug gest the possibility that intimal proliferation may be attenuated by g lucocorticoids.