SMTP ( Stachybotrys microspora triprenyl phenol) enhances clot clearance in a pulmonary embolism model in rats
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ORIGINAL BASIC RESEARCH
Open Access
SMTP (Stachybotrys microspora triprenyl phenol) enhances clot clearance in a pulmonary embolism model in rats Weimin Hu1, Ritsuko Narasaki1, Naoko Nishimura2 and Keiji Hasumi1,2*
Abstract Background: Stachybotrys microspora triprenyl phenols (SMTPs) are a novel family of small molecules that enhance both activation and fibrin-binding of plasminogen. While their effects on fibrinolysis have been characterized in vitro, little is known about their activity in vivo with respect to plasminogen activation and blood clot clearance. Results: To select a potent SMTP congener for the evaluation of its action in vitro and in vivo, we tested several SMTP congeners with distinct structural properties for their effects on plasminogen activation. As a result, SMTP-7 (orniplabin) was found to have distinguished activity. Several lines of biochemical evidence supported the idea that SMTP-7 acted as a plasminogen modulator. SMTP-7 elevated plasma level of plasmin-a2-antiplasmin complex, an index of plasmin formation in vivo, 1.5-fold in mice after the intravenous injections at doses of 5 and 10 mg kg-1. In a rat pulmonary embolism model, SMTP-7 (5 mg kg-1) enhanced the rate of clot clearance ~3-fold in the absence of exogenous plasminogen activator. Clot clearance was enhanced further by 5 mg kg-1 of SMTP-7 in combination with single-chain urokinase-type plasminogen activator. Conclusions: Our results show that SMTP-7 is a superior plasminogen modulator among the SMTP family compounds and suggest that the agent enhances plasmin generation in vivo, leading to clearance of thrombi in a model of pulmonary embolism. Keywords: plasminogen, fibrinolysis, thrombolysis, thromboembolism
Background The plasminogen/plasmin system plays a central role in blood clot lysis [1,2]. Plasminogen is a single-chain glycoprotein consisting of an N-terminal PAN domain, five homologous kringle domains, and a trypsin-like serine protease domain. Plasminogen is converted to the active enzyme plasmin by the specific cleavage of the Arg561Val562 bond by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). The binding of plasminogen to fibrin and cell surfaces, mediated by kringle domains in plasminogen, localizes fibrinolytic activity on fibrin and cell surfaces [3]. Plasminogen adopts a tight conformation due to an intramolecular interaction between a lysine residue (Lys50 and/or * Correspondence: [email protected] 1 Department of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwaicho, Fuchu, Tokyo 183-8509, Japan Full list of author information is available at the end of the article
Lys62) in the PAN domain and a lysine binding site in the fifth kringle domain [4,5]. The tight conformation of the plasminogen molecule attenuates its activation and interaction with fibrin and cellular receptors [3,6]. Lysine analogs such as 6-aminohexanoic acid bind to lysine binding sites in kringle domains and induce a large-scale conformational change in plasminogen [7,8], facilita
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