title: Increased plasmin and serine proteinase activity during flow-induced intimal atrophy in baboon PTFE grafts.
abstract: High blood flow causes intimal atrophy and loss of extracellular matrix in PTFE aortoiliac grafts. We have investigated whether matrix-degrading proteinases are altered in this baboon model of atrophy using zymography, western analysis, and a versican degradation assay. After four days of high flow, urokinase was increased and plasminogen activator inhibitor-1 was decreased in the intima. Plasminogen was increased after seven days. Pro-matrix metalloproteinase (MMP)-2, activated MMP-2, and proMMP-9 levels were modestly increased by high flow at 7 days, whereas MMP-3 and tissue inhibitor of metalloproteinases-1 were not altered. Extracts of 4-day high-flow intimas degraded more 35S-methionine-labeled versican than low-flow intimal extracts, and this activity was inhibited by AEBSF, a serine proteinase inhibitor, and a plasmin antibody. In contrast, this activity was not inhibited by the MMP inhibitor, BB-94 (Batimastat). These data suggest that serine proteinases, including plasmin, may be largely responsible for extracellular matrix degradation in this primate model of flow-induced intimal atrophy.
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Washington, Seattle 98195-6410, USA. rkenagy@u.washington.edu
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kenagy
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.forename: Mark G
authors.initials: MG
authors.lastname: Davies
authors.forename: Scott A
authors.initials: SA
authors.lastname: Berceli
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Hawkins
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Clowes
mesh_terms: D000818:Animals; D001284:Atrophy; D001807:Blood Vessel Prosthesis; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D007083:Iliac Artery; D037181:Lectins, C-Type; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010215:Papio; D016491:Peripheral Vascular Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D010960:Plasminogen Activators / Q000378:metabolism; D011138:Polytetrafluoroethylene; D011480:Protease Inhibitors / Q000378:metabolism; D012039:Regional Blood Flow; D012697:Serine Endopeptidases / Q000378:metabolism*; D017539:Tunica Intima / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D053675:Versicans
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D037181:Lectins, C-Type; D011480:Protease Inhibitors; D053675:Versicans; D011138:Polytetrafluoroethylene; D010960:Plasminogen Activators; D012697:Serine Endopeptidases; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases