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2 results on '"MESH: 6-Aminocaproic Acid"'

1. Fibrinolytic cross-talk: a new mechanism for plasmin formation

Author

Romaric Lacroix, Tiphaine Dejouvencel, Laurent Plawinski, H. Roger Lijnen, Loïc Doeuvre, Eduardo Anglés-Cano, Françoise Dignat-George, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie de l'Endothelium, Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre-Imagerie, Neurosciences, et Application aux Pathologies (CI-NAPS - UMR 6232), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Molecular and Vascular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Inserm European Community's Seventh Framework Programme (FP7/2007-2013) Excellentie financiering, KU Leuven Lower-Normandy Regional Council, European Project: 201024,EC:FP7:HEALTH,FP7-HEALTH-2007-A,ARISE(2008), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)

Subjects
MESH: Signal Transduction, Plasmin, medicine.medical_treatment, MESH: Antifibrinolytic Agents, urokinase, Cell Communication, MESH: Fibrinolysin, 030204 cardiovascular system & hematology, Biochemistry, MESH: Fibrinolysis, Mice, 0302 clinical medicine, Antifibrinolytic agent, MESH: Plasminogen, MESH: Animals, Fibrinolysin, Cells, Cultured, 0303 health sciences, biology, medicine.diagnostic_test, Chemistry, Fibrinolysis, MESH: Plasminogen Activators, lysine-binding site, Hematology, Antifibrinolytic Agents, Extracellular Matrix, Cell biology, Aminocaproic Acid, platelets, plasminogen, monocytes, Signal Transduction, MESH: Cells, Cultured, medicine.drug, Proteolysis, MESH: Receptor Cross-Talk, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Extracellular Matrix, endothelial microparticles, Article, MESH: Urokinase-Type Plasminogen Activator, Plasminogen Activators, 03 medical and health sciences, MESH: 6-Aminocaproic Acid, MESH: Cell Communication, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, Urokinase, MESH: Humans, Activator (genetics), Receptor Cross-Talk, Cell Biology, Urokinase-Type Plasminogen Activator, Fibronectin, MESH: Protein Processing, Post-Translational, biology.protein, Protein Processing, Post-Translational, Plasminogen activator
Abstract

Fibrinolysis and pericellular proteolysis depend on molecular coassembly of plasminogen and its activator on cell, fibrin, or matrix surfaces. We report here the existence of a fibrinolytic cross-talk mechanism bypassing the requirement for their molecular coassembly on the same surface. First, we demonstrate that, despite impaired binding of Glu-plasminogen to the cell membrane by ϵ-aminocaproic acid (ϵ-ACA) or by a lysine-binding site–specific mAb, plasmin is unexpectedly formed by cell-associated urokinase (uPA). Second, we show that Glu-plasminogen bound to carboxy-terminal lysine residues in platelets, fibrin, or extracellular matrix components (fibronectin, laminin) is transformed into plasmin by uPA expressed on monocytes or endothelial cell–derived microparticles but not by tissue-type plasminogen activator (tPA) expressed on neurons. A 2-fold increase in plasmin formation was observed over activation on the same surface. Altogether, these data indicate that cellular uPA but not tPA expressed by distinct cells is specifically involved in the recognition of conformational changes and activation of Glu-plasminogen bound to other biologic surfaces via a lysine-dependent mechanism. This uPA-driven cross-talk mechanism generates plasmin in situ with a high efficiency, thus highlighting its potential physiologic relevance in fibrinolysis and matrix proteolysis induced by inflammatory cells or cell-derived microparticles.

Published
2010
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2. Delivery of steric block morpholino oligomers by (R-X-R)4 peptides: structure-activity studies

Author

Leonid V. Chernomordik, Hong M. Moulton, Paul Prevot, Bernard Lebleu, Rachida Abes, Kamran Melikov, Philippe Clair, Derek S. Youngblood, Patrick L. Iversen, Saïd Abes, Sung-Tae Yang, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), State Key Lab of Estuarine and Coastal Research, State Key Laboratoy of Estuarine and Coastal Research, East China Normal University [Shangaï] (ECNU), University of Maryland [College Park], University of Maryland System, Centre Camille Jullian - Histoire et archéologie de la Méditerranée et de l'Afrique du Nord de la protohistoire à la fin de l'Antiquité (CCJ), Aix Marseille Université (AMU)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique pour l'Entreprise et les Systèmes de Production (LIESP), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon, Interaction Collaborative, Teleformation, Teleactivites (ICTT), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-École Centrale de Lyon (ECL), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-École Centrale de Lyon (ECL)

Subjects
MESH: Hydrogen-Ion Concentration, MESH: Heparin, Morpholino, Oligonucleotides, 01 natural sciences, chemistry.chemical_compound, MESH: Structure-Activity Relationship, MESH: Oligonucleotides, Internalization, media_common, 0303 health sciences, MESH: Peptides, MESH: Arginine, Stereoisomerism, Heparan sulfate, Hydrogen-Ion Concentration, MESH: Amides, Biochemistry, RNA splicing, Aminocaproic Acid, Hydrophobic and Hydrophilic Interactions, RNase P, media_common.quotation_subject, Morpholines, MESH: Biological Transport, MESH: Morpholines, Endosomes, MESH: Phosphoric Acids, Biology, Arginine, 03 medical and health sciences, Structure-Activity Relationship, MESH: 6-Aminocaproic Acid, Genetics, Structure–activity relationship, Humans, Phosphoric Acids, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, MESH: Hydrophobicity, MESH: Humans, 010405 organic chemistry, Oligonucleotide, Heparin, Phosphoramidate, Biological Transport, Amides, MESH: Stereoisomerism, 0104 chemical sciences, MESH: Hela Cells, chemistry, MESH: Endosomes, Liposomes, MESH: Liposomes, Peptides, HeLa Cells
Abstract

International audience; Redirecting the splicing machinery through the hybridization of high affinity, RNase H- incompetent oligonucleotide analogs such as phosphoramidate morpholino oligonucleotides (PMO) might lead to important clinical applications. Chemical conjugation of PMO to arginine-rich cell penetrating peptides (CPP) such as (R-Ahx-R)(4) (with Ahx standing for 6-aminohexanoic acid) leads to sequence-specific splicing correction in the absence of endosomolytic agents in cell culture at variance with most conventional CPPs. Importantly, (R-Ahx-R)(4)-PMO conjugates are effective in mouse models of various viral infections and Duchenne muscular dystrophy. Unfortunately, active doses in some applications might be close to cytotoxic ones thus presenting challenge for systemic administration of the conjugates in those clinical settings. Structure-activity relationship studies have thus been undertaken to unravel CPP structural features important for the efficient nuclear delivery of the conjugated PMO and limiting steps in their internalization pathway. Affinity for heparin (taken as a model heparan sulfate), hydrophobicity, cellular uptake, intracellular distribution and splicing correction have been monitored. Spacing between the charges, hydrophobicity of the linker between the Arg-groups and Arg-stereochemistry influence splicing correction efficiency. A significant correlation between splicing correction efficiency, affinity for heparin and ability to destabilize model synthetic vesicles has been observed but no correlation with cellular uptake has been found. Efforts will have to focus on endosomal escape since it appears to remain the limiting factor for the delivery of these splice-redirecting ON analogs.

Published
2008
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