title: Inhibition of interleukin-1beta convertase is associated with decrease of neointimal hyperplasia after coronary artery stenting in pigs.
abstract: Inhibition of IL-1beta convertase has been shown to decrease inflammation and apoptosis, which are features of the neointimal development after vascular interventions. The aim of our study was to reduce neointimal proliferation after stenting of the porcine coronary artery, using the irreversible IL-1beta convertase and caspase-1 inhibitor acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloromethyl-ketone (Ac-YVAD-cmk). Before coronary stent implantation, 8 pigs received an intracoronary infusion of 50 mg Ac-YVAD-cmk into the left coronary artery (group 1, n = 8), while 8 animals served as untreated controls (group 2). After 4 weeks, coronary angiography and intracoronary ultrasound (IVUS) with 3D measurements were performed. IVUS revealed a smaller in-stent intimal volume (27.3 +/- 11.6 vs. 75.8 +/- 18.4 mm3, p < 0.005) and a decreased maximal percentage area stenosis (36.1 +/- 8.5 vs. 69.0 +/- 8.2%, p < 0.001) in group 1 vs. group 2. A smaller maximal neointimal thickness (0.63 +/- 0.28 vs. 1.75 +/- 0.94 mm, p < 0.005) and a decreased maximal neointimal area (2.14 +/- 1.29 vs. 5.03 +/- 1.92 mm2, p < 0.005), assessed by computerized planimetry, were found in group 1 vs. group 2. Lower apoptotic indices of the neointimal cells were observed in the treated animals (3.0 vs. 13.4% of total intimal cells, p < 0.05). The coronary arterial tissue IL-1beta level was significantly decreased in the animals treated with Ac-YVAD-cmk (0.254 +/- 0.162 vs. 0.463 +/- 0.307 pg/mg protein, p < 0.05), and exhibited a positive linear correlation (r = 0.581, p = 0.013) with the in-stent plaque volume. In conclusion, intracoronary administration of Ac-YVAD-cmk before coronary artery stenting results in significantly decreased neointimal hyperplasia due to the inhibition of local IL-1beta production and decreased neointimal apoptosis.
authors.affiliation: Division of Cardiology, 2nd Department of Internal Medicine, University of Vienna Medical Center, Vienna, Austria. mariann.gyongyosi@univie.ac.at
authors.forename: Mariann
authors.initials: M
authors.lastname: Gyöngyösi
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperker
authors.forename: Csaba
authors.initials: C
authors.lastname: Csonka
authors.forename: Diana
authors.initials: D
authors.lastname: Bonderman
authors.forename: Irene
authors.initials: I
authors.lastname: Lang
authors.forename: Christoph
authors.initials: C
authors.lastname: Strehblow
authors.forename: Christopher
authors.initials: C
authors.lastname: Adlbrecht
authors.forename: Maryam
authors.initials: M
authors.lastname: Shirazi
authors.forename: Ursula
authors.initials: U
authors.lastname: Windberger
authors.forename: Stephan
authors.initials: S
authors.lastname: Marlovits
authors.forename: Michael
authors.initials: M
authors.lastname: Gottsauner-Wolf
authors.forename: Paul
authors.initials: P
authors.lastname: Wexberg
authors.forename: Mark
authors.initials: M
authors.lastname: Kockx
authors.forename: Peter
authors.initials: P
authors.lastname: Ferdinandy
authors.forename: Dietmar
authors.initials: D
authors.lastname: Glogar
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000493:pharmacokinetics*; D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D017023:Coronary Angiography; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000473:pathology*; D006965:Hyperplasia; D015607:Stents; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D018084:Ultrasonography, Interventional
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone