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Research Article Free access | 10.1172/JCI1584

Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis.

A H Baker, A B Zaltsman, S J George, and A C Newby

Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Marlborough Road, Bristol BS2 8HW, United Kingdom. A.H.Baker@bris.ac.uk

Find articles by Baker, A. in: JCI | PubMed | Google Scholar

Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Marlborough Road, Bristol BS2 8HW, United Kingdom. A.H.Baker@bris.ac.uk

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Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Marlborough Road, Bristol BS2 8HW, United Kingdom. A.H.Baker@bris.ac.uk

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Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Marlborough Road, Bristol BS2 8HW, United Kingdom. A.H.Baker@bris.ac.uk

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Published March 15, 1998 - More info

Published in Volume 101, Issue 6 on March 15, 1998
J Clin Invest. 1998;101(6):1478–1487. https://doi.org/10.1172/JCI1584.
© 1998 The American Society for Clinical Investigation
Published March 15, 1998 - Version history
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Abstract

Tissue inhibitors of metalloproteinases (TIMPs) are a family of closely related secreted proteins that limit matrix metalloproteinase (MMP) activity and also have direct effects on cell growth. We used the highly efficient adenoviral delivery system to overexpress individual TIMPs from the cytomegalovirus immediate early promoter in rat aortic smooth muscle cells. Overexpression of TIMP-1, -2, or -3, or a synthetic MMP inhibitor similarly inhibited SMC chemotaxis and invasion through reconstituted basement membrane. TIMP-1 overexpression did not effect cell proliferation. By contrast, TIMP-2 caused a dose-dependent reduction in proliferation, an effect not mimicked by a synthetic MMP inhibitor. TIMP-3 overexpression induced DNA synthesis, and promoted SMC death by apoptosis, a phenotype reproduced by adding TIMP-3 to uninfected cells, but not by a synthetic MMP inhibitor. Our study is the first to compare systematically the effect of overexpression of three TIMPs in any cell. We found similar effects on invasion mediated by inhibition of MMP activity, but widely divergent effects on proliferation and death through actions of TIMP-2 and -3 independent of MMP inhibition. These findings have important implications for the physiological roles of TIMPs and their use in gene therapy.

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