Role of MT1-MMP in Estrogen-Mediated Cellular Processes of Intimal Hyperplasia

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• 作者：Deidra J.H. Mountain ; Ph.D. ; Stacy S. Kirkpatrick ; B.S. ; Michael B. Freeman ; M.D. ; Scott L. Stevens ; M.D. ; Mitchell H. Goldman ; M.D. ; Oscar H. Grandas ; M.D. ; ^{OGrandas@utmck.edu}
• 关键词：matrix metalloproteinase ; MT1-MMP ; gene silencing ; estrogen ; intimal hyperplasia
• 刊名：Journal of Surgical Research
• 出版年：2012
• 期刊代码：299_00224804
• 类别：med
• 出版时间：April, 2012
• 卷：173
• 期：2
• 页码：224-231
• 文件大小：335 K

摘要

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Background

Hormone replacement therapy increases intimal hyperplasia (IH) following vascular intervention. Matrix metalloproteinases (MMPs) play a role in IH development. We have shown estrogen up-regulates MT1-MMP expression, a transmembrane protein that activates MMP-2, and increases vascular smooth muscle cell (VSMC) collagen invasion via increased MMP-2 activity. Here we hypothesize inhibition of MT1-MMP will prevent hormonally-stimulated increased MMP-2 activation and the downstream cellular processes of IH pathogenesis.

Methods

VSMCs from a postmenopausal donor were transfected with MT1-MMP or negative control siRNAs, treated with estrogen (Est), analyzed by q-PCR, Western blot, zymography, migration, invasion, and proliferation assays.

Results

Est treatment of MT1-MMP silenced cells still resulted in increased MT1-MMP expression (C = 41%卤 4%; Est = 52%卤 2%; P < 0.05). Silencing of MT1-MMP decreased basal MMP-2 activity (nonsilenced = 100%; MT1-silenced = 87%卤 3%; P < 0.05) but had no effect on basal invasion or proliferation. Est treatment of MT1-MMP silenced cells still resulted in increased MMP-2 activity (C = 87%卤 3%; Est = 101%卤 4%; P < 0.05) and invasion (C = 89%卤 6%; Est = 109%卤 3%; P聽< 0.05) compared with MT1-MMP silenced control cells. However, silencing of MT1-MMP did inhibit Est- and serum-stimulated proliferation (C = 106%卤 18%; Est = 104%卤 16%; FBS = 121%卤 24%; P = NS).

Conclusion

Silencing of MT1-MMP in aged VSMCs results in impaired but not complete inhibition of basal and Est-stimulated increases in MMP-2 activity. Other mechanisms appear to be playing a role in hormonally-regulated cellular processes of IH pathogenesis. Future studies will target other signaling cascades, with the goal of identifying mechanisms responsible for hormonally-modulated unbalanced MMPs. In vivo manipulation of the expression patterns聽of MT1-MMP will be examined for the prevention of IH in animal models of vascular disease.