This Article Full Text Full Text (PDF) All Versions of this Article: 109/1/108    most recent 01.CIR.0000105724.30980.CDv1 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 Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Beohar, N. Articles by Bonow, R. O. Search for Related Content PubMed PubMed Citation Articles by Beohar, N. Articles by Bonow, R. O. Related Collections Restenosis Animal models of human disease Apoptosis

(Circulation. 2004;109:108-113.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Antirestenotic Effects of a Locally Delivered Caspase Inhibitor in a Balloon Injury Model

Nirat Beohar, MD; James D. Flaherty, MD; Charles J. Davidson, MD; Robert C. Maynard, MD; Joel D. Robbins, MD; Atman P. Shah, MD; James W. Choi, MD; Lee A. MacDonald, MD; Jesse P. Jorgensen, MD; Jack V. Pinto, MD; Sonal Chandra, MD; Heather M. Klaus, MD; Norman C. Wang, MD; Kathleen R. Harris, BS; Robert Decker, PhD; Robert O. Bonow, MD

From Feinberg School of Medicine, Northwestern University, Chicago, Ill.

Correspondence to Nirat Beohar, MD, Feinberg School of Medicine of Northwestern University, Department of Medicine, Division of Cardiology, 251 E Huron St, Feinberg Pavilion 8-526, Chicago, IL 60611. E-mail n-beohar{at}northwestern.edu

Received May 28, 2003; revision received August 25, 2003; accepted August 26, 2003.

Background— The precise role of arterial barotrauma-mediated apoptosis in causing restenosis is unclear. The purpose of this study was to determine if a link exists between angioplasty-mediated medial smooth muscle cell apoptosis and subsequent neointimal hyperplasia.

Methods and Results— Bilateral iliac artery angioplasty was performed in 25 male New Zealand White rabbits. Simultaneous with balloon injury, each artery was treated locally with either the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone (ZVAD-fmk) or control. In the acute cohort that was survived to 4 hours (n=10, 7 high dose and 3 low dose), an apoptotic index was calculated using the terminal deoxynucleotidyl TUNEL method. In the intermediate cohort that was survived to 2 weeks (n=5), luminal reendothelialization was measured via CD-31 staining. In the chronic cohort that was survived to 4 weeks (n=10), neointimal area was measured. In the acute cohort, there was a 40% reduction in the apoptotic index with high-dose ZVAD-fmk (P=0.008) and a 33% reduction with low-dose ZVAD-fmk (P=0.08). At 2 weeks, there was no significant difference in the degree of luminal reendothelialization. However, at 4 weeks, there was a 33% (0.33±0.23 versus 0.22±0.20 mm²) (P<0.005) reduction in neointimal area in ZVAD-fmk–treated arteries.

Conclusions— The local delivery of ZVAD-fmk during balloon injury inhibits smooth muscle cell apoptosis. This corresponds to a significant reduction in neointimal proliferation seen at 4 weeks without a significant change in the degree of reendothelialization at 2 weeks.

Key Words: angioplasty • apoptosis • restenosis

This article has been cited by other articles:

				A. Schober Chemokines in Vascular Dysfunction and Remodeling Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1950 - 1959. [Abstract] [Full Text] [PDF]

				D. G. Sedding, M. Homann, U. Seay, H. Tillmanns, K. T. Preissner, and R. C. Braun-Dullaeus Calpain counteracts mechanosensitive apoptosis of vascular smooth muscle cells in vitro and in vivo FASEB J, February 1, 2008; 22(2): 579 - 589. [Abstract] [Full Text] [PDF]

				T. G. Nuhrenberg, N. Langwieser, J. B.K. Schwarz, Y. Hou, P. Frank, F. Sorge, S. Matschurat, S. Seidl, A. Kastrati, A. Schomig, et al. EMAP-II downregulation contributes to the beneficial effects of rapamycin after vascular injury Cardiovasc Res, February 1, 2008; 77(3): 580 - 589. [Abstract] [Full Text] [PDF]

				R. Kadirvel, Y.-H. Ding, D. Dai, D. A. Lewis, H. J. Cloft, and D. F. Kallmes Molecular Indices of Apoptosis Activation in Elastase-Induced Aneurysms After Embolization With Platinum Coils Stroke, October 1, 2007; 38(10): 2787 - 2794. [Abstract] [Full Text] [PDF]

				N. Urao, M. Okigaki, H. Yamada, Y. Aadachi, K. Matsuno, A. Matsui, S. Matsunaga, K. Tateishi, T. Nomura, T. Takahashi, et al. Erythropoietin-Mobilized Endothelial Progenitors Enhance Reendothelialization via Akt-Endothelial Nitric Oxide Synthase Activation and Prevent Neointimal Hyperplasia Circ. Res., June 9, 2006; 98(11): 1405 - 1413. [Abstract] [Full Text] [PDF]

				A K Mitra and D K Agrawal In stent restenosis: bane of the stent era. J. Clin. Pathol., March 1, 2006; 59(3): 232 - 239. [Abstract] [Full Text] [PDF]

				D. K. Jagadeesha, T. E. Lindley, J. DeLeon, R. V. Sharma, F. Miller, and R. C. Bhalla Tempol therapy attenuates medial smooth muscle cell apoptosis and neointima formation after balloon catheter injury in carotid artery of diabetic rats Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1047 - H1053. [Abstract] [Full Text] [PDF]

				R. Ollinger, M. Bilban, A. Erat, A. Froio, J. McDaid, S. Tyagi, E. Csizmadia, A. V. Graca-Souza, A. Liloia, M. P. Soares, et al. Bilirubin: A Natural Inhibitor of Vascular Smooth Muscle Cell Proliferation Circulation, August 16, 2005; 112(7): 1030 - 1039. [Abstract] [Full Text] [PDF]

				A. Zernecke, A. Schober, I. Bot, P. von Hundelshausen, E. A. Liehn, B. Mopps, M. Mericskay, P. Gierschik, E. A. Biessen, and C. Weber SDF-1{alpha}/CXCR4 Axis Is Instrumental in Neointimal Hyperplasia and Recruitment of Smooth Muscle Progenitor Cells Circ. Res., April 15, 2005; 96(7): 784 - 791. [Abstract] [Full Text] [PDF]