This Article Full Text Full Text (PDF) All Versions of this Article: 25/4/754    most recent 01.ATV.0000157582.33180.a9v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnson, T. W. Articles by Oberhoff, M. Search for Related Content PubMed PubMed Citation Articles by Johnson, T. W. Articles by Oberhoff, M. Pubmed/NCBI databases Medline Plus Health Information Genes and Gene Therapy

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:754.)
© 2005 American Heart Association, Inc.

Vascular Biology

Stent-Based Delivery of Tissue Inhibitor of Metalloproteinase-3 Adenovirus Inhibits Neointimal Formation in Porcine Coronary Arteries

Thomas W. Johnson; Yin Xiong Wu; Christian Herdeg; Andreas Baumbach; Andrew C. Newby; Karl R. Karsch; Martin Oberhoff

From Bristol Heart Institute (T.W.J., Y.X.W., A.B., A.C.N., K.R.K., M.O.), University of Bristol, Bristol, UK; and the Department of Cardiology (C.H.), University of Tübingen, Tübingen, Germany.

Correspondence to Professor Karl R. Karsch, Bristol Heart Institute, University of Bristol, Bristol, UK, BS2 8HW. E-mail K.R.Karsch{at}bristol.ac.uk

Background— Stent-based antiproliferative therapy appears to decrease in-stent restenosis. However, alternative approaches might produce equivalent efficacy with better long-term safety. In previous work, an adenovirus capable of expressing the tissue inhibitor of metalloproteinase-3 (RAdTIMP-3) inhibited neointima formation in cell cultures and porcine saphenous vein grafts. RAdTIMP-3 decreased smooth muscle cell migration, stabilized the extracellular matrix, and uniquely promoted apoptosis. The current study developed eluting stent technology to deliver RAdTIMP-3 during stenting of pig coronary arteries.

Methods and Results— Binding of virus to and elution from stents and transduction of pig coronary arteries were confirmed using ß-galactosidase as a reporter gene in vitro and in vivo. Deployment of RAdTIMP-3–coated stents increased apoptosis and reduced neointimal cell density, but did not increase inflammation or proliferation compared with ß-galactosidase–expressing adenovirus (RAdlacZ). Neointimal area after 28 days was significantly reduced to 1.27±0.19 mm² with RAdTIMP-3 versus 2.61±0.31 mm² with RAdlacZ stents (P<0.001) and 2.12±0.20 mm² with bare stents (P<0.005).

Conclusions— Our results demonstrate for the first time to our knowledge the feasibility of adenovirus-coated stent technology and highlight the potential of TIMP-3 to produce significant inhibition of in-stent neointima formation.

We developed eluting-stent technology to deliver an adenovirus capable of TIMP-3 overexpression and investigated its effect on restenosis. The technology resulted in effective in vitro and in vivo transduction. TIMP-3 overexpression increased apoptosis and reduced neointimal formation. Our results demonstrate for the first time to our knowledge the feasibility of adenovirus-eluting stent technology.

Key Words: gene therapy • metalloproteinases • restenosis • stents • viruses

This article has been cited by other articles:

				Y. Takemoto, H. Kawata, T. Soeda, K. Imagawa, S. Somekawa, Y. Takeda, S. Uemura, M. Matsumoto, Y. Fujimura, J.-i. Jo, et al. Human Placental Ectonucleoside Triphosphate Diphosphohydrolase Gene Transfer via Gelatin-Coated Stents Prevents In-Stent Thrombosis Arterioscler. Thromb. Vasc. Biol., June 1, 2009; 29(6): 857 - 862. [Abstract] [Full Text] [PDF]

				I. Fishbein, I. Alferiev, M. Bakay, S. J. Stachelek, P. Sobolewski, M. Lai, H. Choi, I. -W. Chen, and R. J. Levy Local Delivery of Gene Vectors From Bare-Metal Stents by Use of a Biodegradable Synthetic Complex Inhibits In-Stent Restenosis in Rat Carotid Arteries Circulation, April 22, 2008; 117(16): 2096 - 2103. [Abstract] [Full Text] [PDF]

				V. Kundumani-Sridharan, D. Wang, M. Karpurapu, Z. Liu, C. Zhang, N. Dronadula, and G. N. Rao Suppression of Activation of Signal Transducer and Activator of Transcription-5B Signaling in the Vessel Wall Reduces Balloon Injury-Induced Neointima Formation Am. J. Pathol., October 1, 2007; 171(4): 1381 - 1394. [Abstract] [Full Text] [PDF]

				R R Anis and K R Karsch The future of drug eluting stents Heart, May 1, 2006; 92(5): 585 - 588. [Abstract] [Full Text] [PDF]

				I. Fishbein, I. S. Alferiev, O. Nyanguile, R. Gaster, J. M. Vohs, G. S. Wong, H. Felderman, I-W. Chen, H. Choi, R. L. Wilensky, et al. Bisphosphonate-mediated gene vector delivery from the metal surfaces of stents PNAS, January 3, 2006; 103(1): 159 - 164. [Abstract] [Full Text] [PDF]