Participation of a galectin-dependent mechanism in the hepatic clearance of tissue-type plasminogen activator and plasma kallikrein

Nagaoka, Márcia Regina; Strital, Erika; Kouyoumdjian, Maria; Borges, Durval Rosa

doi:10.1016/s0049-3848(02)00393-6

Cited by 11 publications

(6 citation statements)

References 30 publications

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“…These effects were observed in both pancreatic cancer and tumor-derived fibroblasts. The interaction between galectins and tPA in thrombogenesis are still unknown 32-33…”

Section: The Galectin Protein Familymentioning

confidence: 99%

Do galectins play a role in venous thrombosis? a review

Díaz¹,

Ramacciotti²,

Wakefield³

2010

Thrombosis Research

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Galectins are a family of carbohydrate-binding proteins that have a high affinity to galactosides on cell surfaces and extra cellular glycoproteins. They are involved in a variety of biological functions, including modulation of cell apoptosis, cell activation and inflammation. Our laboratory has recently identified galectin-3 binding protein (Gal-3BP) as being up-regulated in a microparticle proteomics analysis for deep venous thrombosis (DVT) patients compared to negative controls. P-selectin, another glycoprotein involved in thrombus propagation, has proven a promising target for DVT management and has been widely studied by our group. Galectins are involved in P-selectin expression and can potentially be implicated in the venous thrombogenesis process. The function of galectins, their role in inflammation and thrombosis as well as their potential implications as a new pharmacological target for DVT management are reviewed in this manuscript.

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“…These effects were observed in both pancreatic cancer and tumor-derived fibroblasts. The interaction between galectins and tPA in thrombogenesis are still unknown 32-33…”

Section: The Galectin Protein Familymentioning

confidence: 99%

Do galectins play a role in venous thrombosis? a review

Díaz¹,

Ramacciotti²,

Wakefield³

2010

Thrombosis Research

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“…5) and that lanoteplase was a mutant of t-PA, it would seem that lanoteplase is also taken up by the liver mainly as a protein-bound complex. Alternatively, the ASGP receptor binds to t-PA, and this receptor is known to recognize the structural carbohydrates of t-PA at Thr 61, Arg 184, and Asn 448 (Camani et al, 1998;Nagaoka et al, 2003). Because the carbohydrate at Asn 448 is also retained in lanoteplase, the drug seems to bind to the ASGP receptor.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Hepatic Disposition of Lanoteplase, a Rationally Designed Variant of Tissue Plasminogen Activator in Rodents

Komoriya

Kato²,

Hayashi³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Lanoteplase is a recombinant mutant of tissue-type plasminogen activator (t-PA) that was developed with an aim to overcome the drawback of rapid systemic elimination of t-PA. In this study, we examined the disposition profile of lanoteplase in vivo and the kinetics of receptor-mediated endocytosis (RME) of this recombinant t-PA in vitro to kinetically characterize the mechanism(s) underlying its tissue distribution and elimination. Integration plot analysis of the initial-phase tissue distribution in rats revealed a much lower uptake clearance (CL uptake ) of lanoteplase in the liver than that of t-PA. Rate constants for cell surface binding, internalization, and degradation of lanoteplase were also lower than those for t-PA in primary cultured rat hepatocytes. These results suggest that the improved stability of lanoteplase in vivo could be accounted for by the delay in the RME of this recombinant protein.The CL uptake in the liver decreased with coadministration of lactoferrin, a ligand for the low-density lipoprotein receptor-related protein (LRP) and the asialoglycoprotein (ASGP) receptors in normal mice, and in lrpap1 (؊/؊) mice, which have a hereditary deficiency of LRP; In contrast, CL uptake was not affected by mannose, whereas that of t-PA decreased with both ligands and in the lrpap1 (؊/؊) mice. Thus, the hepatic disposition of lanoteplase seems to be mediated by common specific receptors for t-PA, including LRP and the ASGP receptors, whereas the mannose receptor seems to be only minimally involved in the disposition of lanoteplase.Tissue-type plasminogen activator (t-PA) is a serine protease composed of 527 amino acids, containing five structural domains (the finger domain, the epidermal growth factor domain, the kringle 1 domain, the kringle 2 domain, and the serine protease domain) and three sugar chains at amino acid positions 117, 184, and 448. Because of its potent thrombolytic activity, wild-type t-PA has been widely used as a therapeutic thrombolytic agent for myocardial infarction (Llevadot et al., 2001;Collen and Lijnent, 2004), and it has recently been approved for the treatment of stroke. However, even in such emergent clinical care situations, t-PA must be administered by intravenous infusion because of its short half-life of 3 to 4 min. Consequently, several types of recombinant t-PA proteins have been developed to prolong the plasma retention time and thereby make a rapid bolus administration of t-PA possible.Lanoteplase is one of the mutant forms of t-PA, which was developed with the recombinant DNA technology to achieve such an aim.Lanoteplase was produced by removing the epidermal growth factor domain, a part of the finger domain, and by substituting Gln for the Asn residue at position 117, resulting in a removal of the sugar chain. Despite such a major structural modification, lanoteplase still exhibited a potent thrombolytic activity at much lower dose than t-PA both in vivo and in a rabbit model of jugular vein thrombosis (Furuya et al., 1999). In addition, the efficiency...

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“…The most important is binding to liver cell receptors (LRP1), which are responsible for the short half-life of only 4.5 min [101]. LRP1 plays a major role in clearance, followed by MR [62], galectin [102], and potentially by the asialoglycoprotein receptor [55]. Gp330 is highly homologous to LRP1 and could be responsible for the clearance of t-PA in the kidney [103,104].…”

Section: Tissue Plasminogen Activatormentioning

confidence: 99%

Structural Biology and Protein Engineering of Thrombolytics

Mičan

Toul

Bednář

et al. 2019

Computational and Structural Biotechnology Journal

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Myocardial infarction and ischemic stroke are the most frequent causes of death or disability worldwide. Due to their ability to dissolve blood clots, the thrombolytics are frequently used for their treatment. Improving the effectiveness of thrombolytics for clinical uses is of great interest. The knowledge of the multiple roles of the endogenous thrombolytics and the fibrinolytic system grows continuously. The effects of thrombolytics on the alteration of the nervous system and the regulation of the cell migration offer promising novel uses for treating neurodegenerative disorders or targeting cancer metastasis. However, secondary activities of thrombolytics may lead to life-threatening side-effects such as intracranial bleeding and neurotoxicity. Here we provide a structural biology perspective on various thrombolytic enzymes and their key properties: (i) effectiveness of clot lysis, (ii) affinity and specificity towards fibrin, (iii) biological half-life, (iv) mechanisms of activation/inhibition, and (v) risks of side effects. This information needs to be carefully considered while establishing protein engineering strategies aiming at the development of novel thrombolytics. Current trends and perspectives are discussed, including the screening for novel enzymes and small molecules, the enhancement of fibrin specificity by protein engineering, the suppression of interactions with native receptors, liposomal encapsulation and targeted release, the application of adjuvants, and the development of improved production systems.

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Participation of a galectin-dependent mechanism in the hepatic clearance of tissue-type plasminogen activator and plasma kallikrein

Cited by 11 publications

References 30 publications

Do galectins play a role in venous thrombosis? a review

Do galectins play a role in venous thrombosis? a review

Characterization of the Hepatic Disposition of Lanoteplase, a Rationally Designed Variant of Tissue Plasminogen Activator in Rodents

Structural Biology and Protein Engineering of Thrombolytics

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