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  • Title: 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.
    Author: Nakano T, Raines EW, Abraham JA, Wenzel FG, Higashiyama S, Klagsbrun M, Ross R.
    Journal: J Biol Chem; 1993 Oct 25; 268(30):22941-7. PubMed ID: 8226804.
    Abstract:
    Proliferation of smooth muscle cells (SMCs) in atherosclerosis may be modulated by several growth regulatory molecules. At least two mitogens for SMCs, platelet-derived growth factor (PDGF) A-chain and heparin-binding epidermal growth factor-like growth factor (HB-EGF), can be produced by SMCs themselves and may stimulate smooth muscle proliferation in an autocrine or paracrine fashion. We examined the effects of thrombin, which may be generated at the site of vascular injury during atherogenesis, and the potent anti-inflammatory glucocorticoid, dexamethasone (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 heparin binding mitogenic activity from SMCs. Treatment of SMCs with thrombin 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 growth factor activity. DEX inhibits the thrombin-stimulated release of mitogenic activity in a dose-dependent manner. An enzyme-linked immunoadsorbent assay showed that DEX inhibits both constitutive and thrombin-stimulated release of PDGF-AA. DEX also decreases both constitutive and thrombin-stimulated mRNA levels for PDGF A-chain and HB-EGF and destabilizes the transcripts for both growth factors. A nuclear run-on assay revealed that DEX acts, in addition, to inhibit constitutive and thrombin-stimulated transcription of the PDGF A-chain and HB-EGF genes. Thus, these findings indicate that expression of PDGF A-chain and HB-EGF may be regulated by thrombin and glucocorticoid at the transcription level. Our results are consistent with the involvement of thrombin-induced growth factor expression in neointimal SMC proliferation and suggest the possibility that intimal proliferation may be attenuated by glucocorticoids.
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