Antirestenotic effects of a locally delivered caspase inhibitor in a balloon injury model.
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.


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.
Beohar
Nirat
N
Feinberg School of Medicine of Northwestern University, Department of Medicine, Division of Cardiology, 251 E Huron St, Feinberg Pavilion 8-526, Chicago, Ill 60611, USA. n-beohar@northwestern.edu
Flaherty
James D
JD
Davidson
Charles J
CJ
Maynard
Robert C
RC
Robbins
Joel D
JD
Shah
Atman P
AP
Choi
James W
JW
MacDonald
Lee A
LA
Jorgensen
Jesse P
JP
Pinto
Jack V
JV
Chandra
Sonal
S
Klaus
Heather M
HM
Wang
Norman C
NC
Harris
Kathleen R
KR
Decker
Robert
R
Bonow
Robert O
RO
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D023903:Coronary Restenosis / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries / Q000473:pathology*; D011817:Rabbits; D017539:Tunica Intima / Q000473:pathology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases