Glucocorticoid resistance caused by reduced expression of the glucocorticoid receptor in cells from human vascular lesions

Mechanisms that control the balance between cell proliferation and death ar e important in the development of vascular lesions. Rat primary smooth musc le cells were 80% inhibited by low microgram doses of hydrocortisone (HC) a nd 50% inhibited by nanogram concentrations of transforming growth factor-b eta 1 (TGF-beta 1), although some lines acquired resistance in late passage . However, comparable doses of HC, or TGF-beta 1, failed to inhibit most hu man lesion-derived cell (LDC) lines. In sensitive LDC, HC (10 mu g/mL) inhi bited proliferation by up to 50%, with obvious apoptosis in some lines, and TGF-beta 1 inhibited proliferation by more than 90%. Collagen production, as measured by [H-3]proline incorporation or RIA for type III pro-collagen, was either unaffected or increased in the LDCs by HC, These divergent resp onses between LDC lines were partially explained by the absence of the gluc ocorticoid receptor (GR) and heat shock protein 90 mRNA in 10 of 12 LDC lin es, but the presence of the mineralocorticoid receptor and 11 beta-hydroxys teroid dehydrogenase type II. Western blot analysis confirmed the absence o f the GR protein in cells lacking GR mRNA. Immunohistochemistry of human ca rotid lesions showed high levels of GR in the tunica media, but large areas lacking GR in the fibrous lesion. Considering the absence of the GR in mos t, lines, the effects of HC may be elicited through the mineralocorticoid r eceptor. Functional resistance to the antiproliferative and antifibrotic ef fects of HC may contribute to excessive wound repair in atherosclerosis and restenosis.