title: Hirulog-like peptide reduces restenosis and expression of tissue factor and transforming growth factor-beta in carotid artery of atherosclerotic rabbits.
abstract: Restenosis is responsible to approximately 30% of long-term failure following therapeutic vascular procedures. Thrombosis plays a key role in the development of restenosis. Thrombin-specific inhibitors have been considered as one type of candidates for the prevention of restenosis. Previous studies by our group demonstrated that a novel thrombin-specific inhibitor, hirulog-like peptide (HLP), reduced balloon catheter-induced neointima formation in rat carotid arteries. The present study examined the effect of HLP on angioplasty-induced restenosis in carotid arteries of atherosclerotic rabbits. New Zealand white rabbits were subject to air desiccation of the lumen of the right carotid arteries, then received high cholesterol/fat diet for 3 weeks. The rabbits were intravenously infused with HLP (1.6 mg/(kg/h)) or saline (n=7 per group) for 4 h started before angioplasty which dilated atherosclerotic lesions in right common carotid artery. Four weeks after the angioplasty, neointimal area, stenosis and neointima/media ratio in injured carotid arteries were reduced in atherosclerotic rabbits treated with HLP compared to saline controls by 62, 39 and 59% (P<0.05). The expression of tissue factor (TF) and transforming growth factor (TGF)-beta in the neointima of carotid arteries of rabbits treated with HLP was significantly weaker than saline controls (P<0.05 or <0.01). Activated partial thromboplastin time and bleeding time in HLP-treated rabbits were not significantly prolonged compared to controls. The results of the present study suggest that HLP may substantially reduce angioplasty-induced restenosis in atherosclerotic rabbits without increasing bleeding tendency. The inhibition on the expression of TF and TGF-beta in the neointima of the arterial wall may contribute to the preventive effect of HLP on restenosis in atherosclerotic rabbits.
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Man, Canada R3E 3P4.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Song
authors.initials: S
authors.lastname: Ren
authors.forename: Miranda G
authors.initials: MG
authors.lastname: Ma
authors.forename: Sudharshan
authors.initials: S
authors.lastname: Dharmalingam
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Mengzhou
authors.initials: M
authors.lastname: Xue
authors.forename: John
authors.initials: J
authors.lastname: Ducas
authors.forename: Garry X
authors.initials: GX
authors.lastname: Shen
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D001760:Bleeding Time; D017536:Carotid Artery, Common / Q000378:metabolism* / Q000473:pathology; D016893:Carotid Stenosis / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D006629:Hirudins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology*; D012008:Recurrence; D013925:Thromboplastin / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
chemical_list: D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C479171:hirulog-like peptide; D003094:Collagen; D013925:Thromboplastin; C074619:bivalirudin