title: Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site.
abstract: Many proteins in the fibrinolysis pathway contain antiangiogenic kringle domains. Owing to the high degree of homology between kringle domains, there has been a safety concern that antiangiogenic kringles could interact with common kringle proteins during fibrinolysis leading to adverse effects in vivo. To address this issue, we investigated the effects of several antiangiogenic kringle proteins including angiostatin, apolipoprotein(a) kringles IV(9)-IV(10)-V (LK68), apolipoprotein(a) kringle V (rhLK8) and a derivative of rhLK8 mutated to produce a functional lysine-binding site (Lys-rhLK8) on the entire fibrinolytic process in vitro and analyzed the role of lysine binding. Angiostatin, LK68 and Lys-rhLK8 increased clot lysis time in a dose-dependent manner, inhibited tissue-type plasminogen activator-mediated plasminogen activation on a thrombin-modified fibrinogen (TMF) surface, showed binding to TMF and significantly decreased the amount of plasminogen bound to TMF. The inhibition of fibrinolysis by these proteins appears to be dependent on their functional lysine-binding sites. However, rhLK8 had no effect on these processes owing to an inability to bind lysine. Collectively, these results indicate that antiangiogenic kringles without lysine binding sites might be safer with respect to physiological fibrinolysis than lysine-binding antiangiogenic kringles. However, the clinical significance of these findings will require further validation in vivo.
authors.affiliation: Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin, Kyonggi-do, South Korea.
authors.forename: Jin-Hyung
authors.initials: JH
authors.lastname: Ahn
authors.forename: Ho-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Lee
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Yu
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Lee
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jang-Seong
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D043168:Angiostatins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001054:Apolipoproteins A / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D018082:Kringles; D008239:Lysine; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010958:Plasminogen / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001054:Apolipoproteins A; D010446:Peptide Fragments; D043168:Angiostatins; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D008239:Lysine