Arterial repair after stenting and the effects of GM6001, a matrix metalloproteinase inhibitor.
OBJECTIVE
This study compared the extracellular matrix (ECM) and cellular responses after stenting to balloon angioplasty (BA) and to determine the late effects of matrix metalloproteinase (MMP) inhibition on arterial repair after stenting.


BACKGROUND
Although stenting is the predominant form of coronary intervention, there is limited understanding of the early and late arterial response.


METHODS
In a double-injury rabbit model, adjacent iliac arteries in 87 animals received BA (3.0 mm diameter) or stenting (3.0 mm NIR). Rabbits were treated for 1 week postprocedure with either GM6001 (100 mg/kg per day), an MMP inhibitor or placebo and sacrificed at 1 week or at 10 weeks' postprocedure. Arteries were analyzed for morphometry, collagen content, gelatinase activity, cell proliferation and DNA content.


RESULTS
Stented arteries had significant increases in collagen content (2-fold) at 10 weeks compared to BA-treated arteries. At one week, overall gelatinase activity was increased >2-fold in stented arteries, with both 72 kD and 92 kD gelatinase activity. Stented arteries also had increases in both intimal DNA content (1.5-fold) and absolute cell proliferation (4-fold). Compared to placebo, GM6001 significantly inhibited intimal hyperplasia and intimal collagen content, and it increased lumen area in stented arteries without effects on proliferation rates.


CONCLUSIONS
Stenting causes a more vigorous ECM and MMP response than BA, which involves all layers of the vessel wall. Inhibition by MMP blocks in-stent intimal hyperplasia and offers a novel approach to prevent in-stent restenosis.
Li
Chris
C
Roy and Ann Foss Interventional Cardiology Research Program, Terrence Donnelly Heart Center, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8.
Cantor
Warren J
WJ
Nili
Nafiseh
N
Robinson
Ranga
R
Fenkell
Louis
L
Tran
Yen Le
YL
Whittingham
Heather A
HA
Tsui
Winston
W
Cheema
Asim N
AN
Sparkes
John D
JD
Pritzker
Kenneth
K
Levy
Daniel E
DE
Strauss
Bradley H
BH
D000818:Animals; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division; D003094:Collagen / Q000096:biosynthesis* / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D006965:Hyperplasia; D007083:Iliac Artery / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D015607:Stents / Q000009:adverse effects*; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism
D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D003094:Collagen; D008666:Metalloendopeptidases