This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Biessen, E. A.L. Articles by Kuiper, J. Search for Related Content PubMed PubMed Citation Articles by Biessen, E. A.L. Articles by Kuiper, J.

(Circulation. 1997;95:46-52.)
© 1997 American Heart Association, Inc.

Articles

Antagonists of the Mannose Receptor and the LDL Receptor–Related Protein Dramatically Delay the Clearance of Tissue Plasminogen Activator

Erik A.L. Biessen, PhD; Marco van Teijlingen; Helene Vietsch; Marrie M. Barrett-Bergshoeff; Martin K. Bijsterbosch, PhD; Dingeman C. Rijken, PhD; Theo J.C. van Berkel, PhD; Johan Kuiper, PhD

the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden (E.A.L.B., M.v.T., H.V., M.K.B., T.J.C.v.B., J.K.), and Gaubius Laboratory, TNO Prevention and Health (M.M.B.-B., D.C.R.), Leiden, The Netherlands.

Correspondence to Dr Ir E.A.L. Biessen, Division of Biopharmaceutics, LACDR, University of Leiden, PO Box 9503, 2300 RA Leiden, The Netherlands.

Background Clinical application of tissue plasminogen activator (TPA) as a fibrinolytic agent is complicated by its rapid clearance from the bloodstream, which is caused by TPA liver uptake. The mannose receptor on endothelial liver cells and the LDL receptor–related protein (LRP) on parenchymal liver cells were reported to contribute to liver uptake.

Methods and Results In this study, we addressed whether TPA clearance can be delayed by inhibiting receptor-mediated endocytosis of TPA. A series of cluster mannosides was synthesized, and their affinity for the mannose receptor was determined. A cluster mannoside carrying six mannose groups (M₆L₅) displayed a subnanomolar affinity for the mannose receptor (K_i=0.41±0.09 nmol/L). Preinjection of M₆L₅ (1.2 mg/kg) reduced the clearance of ¹²⁵I-TPA in rats by 60% because of specific inhibition of the endothelial cell uptake. The low toxicity of M₆L₅, combined with its accessible synthesis and high specificity for the mannose receptor, makes it a promising agent to improve the pharmacokinetics of TPA. Blockade of LRP by 39-kD receptor-associated protein (GST-RAP) also inhibited TPA clearance by 60%. Finally, combined preinjection of M₆L₅ and GST-RAP almost completely abolished reduced liver uptake of TPA and delayed its clearance by a factor of 10.

Conclusions It can be concluded that (1) the mannose receptor and LRP appear to be the sole major receptors responsible for TPA clearance and (2) therapeutic levels of TPA can be maintained for a prolonged time span by coadministration of the aforementioned receptor antagonists.

Key Words: plasminogen activators • thrombolysis • cluster mannoside • GST-RAP

This article has been cited by other articles:

				O. E. Akilov, R. E. Kasuboski, C. R. Carter, and M. A. McDowell The role of mannose receptor during experimental leishmaniasis J. Leukoc. Biol., May 1, 2007; 81(5): 1188 - 1196. [Abstract] [Full Text] [PDF]

				J. P. Lopez-Atalaya, B. D. Roussel, C. Ali, E. Maubert, K.-U. Petersen, V. Berezowski, R. Cecchelli, C. Orset, and D. Vivien Recombinant Desmodus rotundus Salivary Plasminogen Activator Crosses the Blood-Brain Barrier Through a Low-Density Lipoprotein Receptor-Related Protein-Dependent Mechanism Without Exerting Neurotoxic Effects Stroke, March 1, 2007; 38(3): 1036 - 1043. [Abstract] [Full Text] [PDF]

				I. Z. A. Pawluczyk, S. R. Patel, and K. P. G. Harris The role of the {alpha}-1 adrenoceptor in modulating human mesangial cell matrix production Nephrol. Dial. Transplant., September 1, 2006; 21(9): 2417 - 2424. [Abstract] [Full Text] [PDF]

				K. Benchenane, V. Berezowski, C. Ali, M. Fernandez-Monreal, J. P. Lopez-Atalaya, J. Brillault, J. Chuquet, A. Nouvelot, E. T. MacKenzie, G. Bu, et al. Tissue-Type Plasminogen Activator Crosses the Intact Blood-Brain Barrier by Low-Density Lipoprotein Receptor-Related Protein-Mediated Transcytosis Circulation, May 3, 2005; 111(17): 2241 - 2249. [Abstract] [Full Text] [PDF]

				V. Llorente-Cortes, M. Otero-Vinas, S. Sanchez, C. Rodriguez, and L. Badimon Low-Density Lipoprotein Upregulates Low-Density Lipoprotein Receptor-Related Protein Expression in Vascular Smooth Muscle Cells: Possible Involvement of Sterol Regulatory Element Binding Protein-2-Dependent Mechanism Circulation, December 10, 2002; 106(24): 3104 - 3110. [Abstract] [Full Text] [PDF]

				J. J. Yang, G. A. Preston, W. F. Pendergraft, M. Segelmark, P. Heeringa, S. L. Hogan, J. C. Jennette, and R. J. Falk Internalization of Proteinase 3 Is Concomitant with Endothelial Cell Apoptosis and Internalization of Myeloperoxidase with Generation of Intracellular Oxidants Am. J. Pathol., February 1, 2001; 158(2): 581 - 592. [Abstract] [Full Text] [PDF]

				M. Lansink, M. Jong, M. Bijsterbosch, M. Bekkers, K. Toet, L. Havekes, J. Emeis, and T. Kooistra Increased Clearance Explains Lower Plasma Levels of Tissue-Type Plasminogen Activator by Estradiol: Evidence for Potently Enhanced Mannose Receptor Expression in Mice Blood, August 15, 1999; 94(4): 1330 - 1336. [Abstract] [Full Text] [PDF]