Effect of Hormones on Matrix Metalloproteinases Gene Regulation in Human Aortic Smooth Muscle Cells

Background Postmenopausal women receiving hormone replacement therapy have more adverse outcomes after vascular reconstructions. Estrogen-binding receptors have been identified on vascular smooth muscle cells (VSMCs), indicating that vascular function may be under direct hormonal control. A key grou...

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Bibliographic Details
Published in:The Journal of surgical research 2008-07, Vol.148 (1), p.94-99
Main Authors: Grandas, Oscar H., M.D, Mountain, Deidra J.H., Ph.D, Kirkpatrick, Stacy S., B.S, Rudrapatna, Vivek S., M.D, Cassada, David C., M.D, Stevens, Scott L., M.D, Freeman, Michael B., M.D, Goldman, Mitchell H., M.D
Format: Article
Language:English
Subjects:
Biological and medical sciences
Blotting, Western
Cell Culture Techniques
estrogen
Estrogens - pharmacology
Female
Gene Expression - drug effects
General aspects
HRT
Humans
Interleukin-1beta - pharmacology
Matrix Metalloproteinase 14 - metabolism
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 3 - metabolism
Matrix Metalloproteinases - metabolism
Medical sciences
MMP
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - enzymology
Postmenopause
Progesterone - pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Surgery
Tissue Inhibitor of Metalloproteinases - metabolism
Up-Regulation
vascular remodeling
VSMC
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Summary:Background Postmenopausal women receiving hormone replacement therapy have more adverse outcomes after vascular reconstructions. Estrogen-binding receptors have been identified on vascular smooth muscle cells (VSMCs), indicating that vascular function may be under direct hormonal control. A key group of enzymes involved in vascular remodeling are matrix metalloproteinases (MMPs). Here we studied the effect of estrogen (Est) and progesterone (Prog) on MMP gene expression in human VSMCs. Methods and results VSMCs were incubated with Est (5 ng/mL), Prog (50 ng/mL), Est+Prog combination (Est/Prog), and interleukin-1β (100 U/mL; IL-1β). Gene array analysis indicated Est+IL-1β increased the expression of MMP-3. Reverse transcriptase-polymer chain reaction (RT-PCR) analyses revealed MMP-3 mRNA levels were significantly increased by Est/Prog+IL-1β treatment. However, Western blot and further RT-PCR analyses indicated no change in MMP-3 in response to hormones alone. RT-PCR analyses revealed membrane type 1 (MT1)-MMP mRNA levels, not MMP-2 or tissue inhibitor of MMP (TIMP), were significantly increased by Est/Prog+IL-1β, and Western blot analyses confirmed a significant increase in MT1-MMP protein in response to Est alone. Conclusion Estrogen and progesterone affect the MMP pathway of VSMCs via isoform specific mechanisms and may lead to unbalanced MMP regulation. Estrogen up-regulates MT1-MMP without a corresponding increase in TIMP-2, known activator and inhibitor of MMP-2, respectively. Additionally, estrogen up-regulates MMP-3 only in the presence of IL-1β. This differential regulation, combined with case-specific variations in degree of inflammatory response, may explain why some women receiving exogenous hormone therapy at the time of vascular interventions are more susceptible to complications.
ISSN:0022-4804
1095-8673
DOI:10.1016/j.jss.2008.03.003