Glucocorticoid resistance caused by reduced expression of the glucocorticoid receptor in cells from human vascular lesions
Arteriosclerosis, Thrombosis, and Vascular Biology
Atherosclerosis; Cell proliferation; Collagen production; Glucocorticoid receptor; Restenosis; Smooth muscle cells; Transforming growth factor- β1
Mechanisms that control the balance between cell proliferation and death are important in the development of vascular lesions. Rat primary smooth muscle cells were 80% inhibited by low microgram doses of hydrocortisone (HC) and 50% inhibited by nanogram concentrations of transforming growth factor- β1 (TGF-β1), although some lines acquired resistance in late passage. However, comparable doses of HC, or TGF-β1, failed to inhibit most human lesion-derived cell (LDC) lines. In sensitive LDC, HC (10 μg/mL) inhibited proliferation by up to 50%, with obvious apoptosis in some lines, and TGF- β1 inhibited proliferation by more than 90%. Collagen production, as measured by [3H]proline incorporation or RIA for type III pro-collagen, was either unaffected or increased in the LDCs by HC. These divergent responses between LDC lines were partially explained by the absence of the glucocorticoid receptor (GR) and heat shock protein 90 mRNA in 10 of 12 LDC lines, but the presence of the mineralocorticoid receptor and 11β- hydroxysteroid dehydrogenase type II. Western blot analysis confirmed the absence of the GR protein in cells lacking GR mRNA. Immunohistochemistry of human carotid 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 most lines, the effects of HC may be elicited through the mineralocorticoid receptor. Functional resistance to the antiproliferative and antifibrotic effects of HC may contribute to excessive wound repair in atherosclerosis and restenosis.
Bray, P., Du, B., Mejia, V., Hao, S., Deutsch, E., Fu, C., Wilson, R., Hanauske-Abel, H., & McCaffrey, T. (1999). Glucocorticoid resistance caused by reduced expression of the glucocorticoid receptor in cells from human vascular lesions. Arteriosclerosis, Thrombosis, and Vascular Biology, 19 (5). http://dx.doi.org/10.1161/01.ATV.19.5.1180