© 1999 American Heart Association, Inc.
Vascular Biology |
Glucocorticoid Resistance Caused by Reduced Expression of the Glucocorticoid Receptor in Cells From Human Vascular Lesions
From the Divisions of Hematology/Oncology (P.J.B., B.D., V.M.M., C.F., T.A.M.) and Cardiology (S.C.H., E.D.), Department of Medicine, and the Division of Pediatric Endocrinology (R.C.W., H.H.-A.), Department of Pediatrics, Cornell University Medical College, New York, NY.
Correspondence to Timothy A. McCaffrey, PhD, Cornell University Medical College, Division of Hematology/Oncology, Room C606, 1300 York Ave, New York, NY 10021. E-mail tamccaf{at}med.cornell.edu
Abstract—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-ß1 (TGF-ß1), although some lines acquired resistance in late passage. However, comparable doses of HC, or TGF-ß1, 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-ß1 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 11ß-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.
Key Words: glucocorticoid receptor • transforming growth factor-ß1 • atherosclerosis • cell proliferation • collagen production • smooth muscle cells • restenosis
This article has been cited by other articles:
 |
|
 |
|
  I. Z. Jaffe, Y. Tintut, B. G. Newfell, L. L. Demer, and M. E. Mendelsohn Mineralocorticoid Receptor Activation Promotes Vascular Cell Calcification Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 799 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Matthews, J. Schwartz, S. Cohen, and T. Seeman Diurnal Cortisol Decline is Related to Coronary Calcification: CARDIA Study. Psychosom Med, September 1, 2006; 68(5): 657 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Girod and D. J. Brotman Does altered glucocorticoid homeostasis increase cardiovascular risk? Cardiovasc Res, November 1, 2004; 64(2): 217 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Du, C. Fu, K. C. Kent, H. Bush Jr., A. H. Schulick, K. Kreiger, T. Collins, and T. A. McCaffrey Elevated Egr-1 in Human Atherosclerotic Cells Transcriptionally Represses the Transforming Growth Factor-beta Type II Receptor J. Biol. Chem., December 8, 2000; 275(50): 39039 - 39047. [Abstract] [Full Text] [PDF]
|
|