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 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.


RESULTS
VSMCs were incubated with Est (5 ng/mL), Prog (50 ng/mL), Est+Prog combination (Est/Prog), and interleukin-1beta (100 U/mL; IL-1beta). Gene array analysis indicated Est+IL-1beta 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-1beta 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-1beta, and Western blot analyses confirmed a significant increase in MT1-MMP protein in response to Est alone.


CONCLUSIONS
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-1beta. 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.
Grandas
Oscar H
OH
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee 37920, USA. Ograndas@mc.utmck.edu
Mountain
Deidra J H
DJ
Kirkpatrick
Stacy S
SS
Rudrapatna
Vivek S
VS
Cassada
David C
DC
Stevens
Scott L
SL
Freeman
Michael B
MB
Goldman
Mitchell H
MH
D015153:Blotting, Western; D018929:Cell Culture Techniques; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D017698:Postmenopause; D011374:Progesterone / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D015854:Up-Regulation
D004967:Estrogens; D053583:Interleukin-1beta; D019714:Tissue Inhibitor of Metalloproteinases; D011374:Progesterone; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14