HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited 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 Add to Personal Folders Download to citation manager Author home page(s): Afshin Ehsan Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ehsan, A. Articles by Dzau, V. J. Search for Related Content PubMed PubMed Citation Articles by Ehsan, A. Articles by Dzau, V. J. Related Collections Coronary disease Molecular biology

J Thorac Cardiovasc Surg 2001;121:714-722
© 2001 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Long-term stabilization of vein graft wall architecture and prolonged resistance to experimental atherosclerosis after E2F decoy oligonucleotide gene therapy

From the Division of Cardiovascular Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Mass.

This work was supported by National Institutes of Health grants HL61661, HL58516, HL59316, HL35610; the Charles and Ellen Collins Fund; and the Edna Mandel Fund. Dr Ehsan is the recipient of the American Heart Association post-doctoral fellowship grant 9820007T. Dr Mann is supported by the William Randolph Hearst Endowment for Young Investigators. Dr Dzau is the recipient of a National Heart, Lung, and Blood Institute MERIT Award.

Received for publication March 15, 2000. Revisions requested June 26, 2000; revisions received Aug 23, 2000. Accepted for publication Aug 31, 2000. Address for reprints: Victor J. Dzau, MD, Tower 1, Office of the Chairman, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, 75 Francis St, Boston, MA 02115 (E-mail: vdzau{at}rics.bwh.harvard.edu).

Abstract

Objective: We tested the hypothesis that a single intraoperative transfection of rabbit vein grafts with a decoy oligonucleotide that blocks cell-cycle gene transactivation by the transcription factor E2F induces long-term stable adaptation that involves medial hypertrophy and a resistance to neointimal hyperplasia and atherosclerosis.
Methods: Jugular vein to carotid artery interposition vein grafts in hypercholesterolemic rabbits were treated, using pressure-mediated delivery, with either E2F decoy oligonucleotide, scrambled oligonucleotide, or vehicle alone. E2F decoy inhibition of cell-cycle gene expression was determined by measuring proliferating cell nuclear antigen upregulation and bromodeoxyuridine incorporation in vascular smooth muscle cells. Neointimal hyperplasia and atherosclerosis were compared between groups at 6 months after operation. Wall stress was derived from the ratio of luminal radius to wall thickness. Normal rabbits exposed to 6 weeks of diet-induced hypercholesterolemia starting 6 months after operation were analyzed in the same manner.
Results: The E2F decoy oligonucleotide, but not scrambled oligonucleotide or vehicle alone, inhibited proliferating cell nuclear antigen expression and smooth muscle cell proliferation. Furthermore, this manipulation of cell-cycle gene expression yielded an inhibition of neointimal hyperplasia and atherosclerotic plaque formation throughout the 6 months of cholesterol feeding. In normocholesterolemic rabbits, vehicle-treated and scrambled oligonucleotide-treated vein grafts remain susceptible to diet-induced atherosclerosis as well, whereas resistance to this disease induction remained stable in genetically engineered grafts.
Conclusion: A single intraoperative pressure-mediated delivery of E2F decoy effectively provides vein grafts with long-term resistance to neointimal hyperplasia and atherosclerosis. These findings suggest that long-term reduction in human vein graft failure rates may be feasible with this ex vivo gene therapy approach.

This article has been cited by other articles:

				T. Miyake, M. Aoki, and R. Morishita Inhibition of anastomotic intimal hyperplasia using a chimeric decoy strategy against NF{kappa}B and E2F in a rabbit model Cardiovasc Res, September 1, 2008; 79(4): 706 - 714. [Abstract] [Full Text] [PDF]

				R. Bhindi, R. G. Fahmy, H. C. Lowe, C. N. Chesterman, C. R. Dass, M. J. Cairns, E. G. Saravolac, L.-Q. Sun, and L. M. Khachigian Brothers in Arms: DNA Enzymes, Short Interfering RNA, and the Emerging Wave of Small-Molecule Nucleic Acid-Based Gene-Silencing Strategies Am. J. Pathol., October 1, 2007; 171(4): 1079 - 1088. [Abstract] [Full Text] [PDF]

				G. J. Murphy, T. W. Johnson, M. H. Chamberlain, S. I. Rizvi, M. Wyatt, S. J. George, G. D. Angelini, K. R. Karsch, M. Oberhoff, and A. C. Newby Short- and long-term effects of cytochalasin D, paclitaxel and rapamycin on wall thickening in experimental porcine vein grafts Cardiovasc Res, February 1, 2007; 73(3): 607 - 617. [Abstract] [Full Text] [PDF]

				T. Schachner, G. Laufer, and J. Bonatti In vivo (animal) models of vein graft disease. Eur. J. Cardiothorac. Surg., September 1, 2006; 30(3): 451 - 463. [Abstract] [Full Text] [PDF]

				T. Schachner Pharmacologic inhibition of vein graft neointimal hyperplasia J. Thorac. Cardiovasc. Surg., May 1, 2006; 131(5): 1065 - 1072. [Abstract] [Full Text] [PDF]

				G. T. Lau and L. Kritharides Efficacy and Safety of Edifoligide JAMA, April 5, 2006; 295(13): 1513 - 1514. [Full Text] [PDF]

				V. R. Conti and G. C. Hunter Gene Therapy and Vein Graft Patency in Coronary Artery Bypass Graft Surgery JAMA, November 16, 2005; 294(19): 2495 - 2497. [Full Text] [PDF]

				PREVENT IV Investigators Efficacy and Safety of Edifoligide, an E2F Transcription Factor Decoy, for Prevention of Vein Graft Failure Following Coronary Artery Bypass Graft Surgery: PREVENT IV: A Randomized Controlled Trial JAMA, November 16, 2005; 294(19): 2446 - 2454. [Abstract] [Full Text] [PDF]

				D. A. Dean Nonviral gene transfer to skeletal, smooth, and cardiac muscle in living animals Am J Physiol Cell Physiol, August 1, 2005; 289(2): C233 - C245. [Abstract] [Full Text] [PDF]

				A. Chandiwal, V. Balasubramanian, Z. K. Baldwin, M. S. Conte, and L. B. Schwartz Gene Therapy for the Extension of Vein Graft Patency: A Review Vascular and Endovascular Surgery, January 1, 2005; 39(1): 1 - 14. [Abstract] [PDF]

				M. S. Conte, T. J. Lorenz, D. F. Bandyk, A. W. Clowes, G. L. Moneta, and B. L. Seely Design and Rationale of the PREVENT III Clinical Trial: Edifoligide for the Prevention of Infrainguinal Vein Graft Failure Vascular and Endovascular Surgery, January 1, 2005; 39(1): 15 - 23. [Abstract] [PDF]

				L. Zhang, K. Peppel, L. Brian, L. Chien, and N. J. Freedman Vein Graft Neointimal Hyperplasia Is Exacerbated by Tumor Necrosis Factor Receptor-1 Signaling in Graft-Intrinsic Cells Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2277 - 2283. [Abstract] [Full Text] [PDF]

				L. Zhang, N. J. Freedman, L. Brian, and K. Peppel Graft-Extrinsic Cells Predominate in Vein Graft Arterialization Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 470 - 476. [Abstract] [Full Text]

				J. A. Petrofski, J. A. Hata, T. R. Gehrig, S. I. Hanish, M. L. Williams, R. B. Thompson, C. J. Parsa, W. J. Koch, and C. A. Milano Gene delivery to aortocoronary saphenous vein grafts in a large animal model of intimal hyperplasia J. Thorac. Cardiovasc. Surg., January 1, 2004; 127(1): 27 - 33. [Abstract] [Full Text] [PDF]

				Z. Jiang, L. Wu, B. L. Miller, D. R. Goldman, C. M. Fernandez, Z. S. Abouhamze, C. K. Ozaki, and S. A. Berceli A novel vein graft model: adaptation to differential flow environments Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H240 - H245. [Abstract] [Full Text] [PDF]

				G. D. Angelini, C. Lloyd, R. Bush, J. Johnson, and A. C. Newby An external, oversized, porous polyester stent reduces vein graft neointima formation, cholesterol concentration, and vascular cell adhesion molecule 1 expression in cholesterol-fed pigs J. Thorac. Cardiovasc. Surg., November 1, 2002; 124(5): 950 - 956. [Abstract] [Full Text] [PDF]

				V. J. Dzau Transcription Factor Decoy Circ. Res., June 28, 2002; 90(12): 1234 - 1236. [Full Text] [PDF]

				N. N. Kipshidze, H.-S. Kim, P. Iversen, H. A. Yazdi, B. Bhargava, G. New, R. Mehran, F. Tio, C. Haudenschild, G. Dangas, et al. Intramural coronary delivery of advanced antisense oligonucleotides reduces neointimal formation in the porcine stent restenosis model J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1686 - 1691. [Abstract] [Full Text] [PDF]

				PREVENT IV Investigators Efficacy and Safety of Edifoligide, an E2F Transcription Factor Decoy, for Prevention of Vein Graft Failure Following Coronary Artery Bypass Graft Surgery: PREVENT IV: A Randomized Controlled Trial JAMA, November 16, 2005; 294(19): 2446 - 2454. [Abstract] [Full Text] [PDF]

				V. R. Conti and G. C. Hunter Gene Therapy and Vein Graft Patency in Coronary Artery Bypass Graft Surgery JAMA, November 16, 2005; 294(19): 2495 - 2497. [Full Text] [PDF]

				A. Ehsan, M. J. Mann, G. Dell'Acqua, K. Tamura, R. Braun-Dullaeus, and V. J. Dzau Endothelial Healing in Vein Grafts: Proliferative Burst Unimpaired by Genetic Therapy of Neointimal Disease Circulation, April 9, 2002; 105(14): 1686 - 1692. [Abstract] [Full Text] [PDF]