The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies

Detalhes bibliográficos
Autor(a) principal: Medina, A. F.
Data de Publicação: 2022
Outros Autores: Salu, B. R., de Brito, M. V., Bonturi, C. R., Meneghetti, M. C.Z., Maffei, F. H.A. [UNESP], Oliva, M. L.V.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1016/j.procbio.2022.08.013
http://hdl.handle.net/11449/241545
Resumo: Coagulation contact pathway inhibitors have aroused interest in the treatment and prevention of thrombosis due to their lower hemorrhagic effects. We investigate the recombinant kallikrein inhibitor (rBbKIm) containing the RGD/RGE motif and its related peptides in arterial thrombosis models. rBbKIm prolonged activated partial thromboplastin time by 3.5 (8.6 µM) and 4.1 times (17.2 µM), and extended the arterial occlusion time in a dose-dependent manner: 2.0 mg/kg (48.83 ± 15.87 min), 4.0 mg/kg (73.06 ± 21.38 min) and 8.0 mg/kg (94.13 ± 11.25 min) compared with control (0.15 M NaCl, 29.70 ± 7.14 min). Similar results were obtained with the RGD-peptide, 2.5 mg/kg (62.85 ± 18.53 min) and 5.0 mg/kg (89.50 ± 8.63 min). Thrombus sizes were decreased in the rBbKIm, RGD-peptide, and fondaparinux (0.7 mg/kg) treated groups, due to reduced adhesion of platelet to the endothelium. ADP-induced platelet aggregation ex vivo was inhibited by both rBbKIm (4.0 mg/kg, 75 %) and the RGD-peptide (5.0 mg/kg, 56 %), and they did not modify the bleeding time in contrast to fondaparinux. rBbKIm and RGD-related-peptide delayed the artery occlusion and reduced the thrombus size without any modification of the bleeding time, thereby impairing the aggregation and/or adhesion of platelets, making them useful for thrombosis therapy.
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spelling The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapiesArterial thrombosisBlood coagulationIntegrinKallikreinPlateletsCoagulation contact pathway inhibitors have aroused interest in the treatment and prevention of thrombosis due to their lower hemorrhagic effects. We investigate the recombinant kallikrein inhibitor (rBbKIm) containing the RGD/RGE motif and its related peptides in arterial thrombosis models. rBbKIm prolonged activated partial thromboplastin time by 3.5 (8.6 µM) and 4.1 times (17.2 µM), and extended the arterial occlusion time in a dose-dependent manner: 2.0 mg/kg (48.83 ± 15.87 min), 4.0 mg/kg (73.06 ± 21.38 min) and 8.0 mg/kg (94.13 ± 11.25 min) compared with control (0.15 M NaCl, 29.70 ± 7.14 min). Similar results were obtained with the RGD-peptide, 2.5 mg/kg (62.85 ± 18.53 min) and 5.0 mg/kg (89.50 ± 8.63 min). Thrombus sizes were decreased in the rBbKIm, RGD-peptide, and fondaparinux (0.7 mg/kg) treated groups, due to reduced adhesion of platelet to the endothelium. ADP-induced platelet aggregation ex vivo was inhibited by both rBbKIm (4.0 mg/kg, 75 %) and the RGD-peptide (5.0 mg/kg, 56 %), and they did not modify the bleeding time in contrast to fondaparinux. rBbKIm and RGD-related-peptide delayed the artery occlusion and reduced the thrombus size without any modification of the bleeding time, thereby impairing the aggregation and/or adhesion of platelets, making them useful for thrombosis therapy.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Department of Biochemistry and Molecular Biology Universidade Federal de São Paulo, SPDepartment of Molecular Biology Universidade Estadual de Minas Gerais, Minas GeraisDepartment of Surgery and Orthopedics Universidade Estadual Paulista, São PauloDepartment of Surgery and Orthopedics Universidade Estadual Paulista, São PauloUniversidade Federal de São Paulo (UNIFESP)Universidade Estadual de Minas GeraisUniversidade Estadual Paulista (UNESP)Medina, A. F.Salu, B. R.de Brito, M. V.Bonturi, C. R.Meneghetti, M. C.Z.Maffei, F. H.A. [UNESP]Oliva, M. L.V.2023-03-01T21:09:15Z2023-03-01T21:09:15Z2022-11-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1-12http://dx.doi.org/10.1016/j.procbio.2022.08.013Process Biochemistry, v. 122, p. 1-12.1359-5113http://hdl.handle.net/11449/24154510.1016/j.procbio.2022.08.0132-s2.0-85136497497Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengProcess Biochemistryinfo:eu-repo/semantics/openAccess2024-08-14T14:19:17Zoai:repositorio.unesp.br:11449/241545Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-14T14:19:17Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies
title The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies
spellingShingle The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies
Medina, A. F.
Arterial thrombosis
Blood coagulation
Integrin
Kallikrein
Platelets
title_short The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies
title_full The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies
title_fullStr The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies
title_full_unstemmed The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies
title_sort The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies
author Medina, A. F.
author_facet Medina, A. F.
Salu, B. R.
de Brito, M. V.
Bonturi, C. R.
Meneghetti, M. C.Z.
Maffei, F. H.A. [UNESP]
Oliva, M. L.V.
author_role author
author2 Salu, B. R.
de Brito, M. V.
Bonturi, C. R.
Meneghetti, M. C.Z.
Maffei, F. H.A. [UNESP]
Oliva, M. L.V.
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade Federal de São Paulo (UNIFESP)
Universidade Estadual de Minas Gerais
Universidade Estadual Paulista (UNESP)
dc.contributor.author.fl_str_mv Medina, A. F.
Salu, B. R.
de Brito, M. V.
Bonturi, C. R.
Meneghetti, M. C.Z.
Maffei, F. H.A. [UNESP]
Oliva, M. L.V.
dc.subject.por.fl_str_mv Arterial thrombosis
Blood coagulation
Integrin
Kallikrein
Platelets
topic Arterial thrombosis
Blood coagulation
Integrin
Kallikrein
Platelets
description Coagulation contact pathway inhibitors have aroused interest in the treatment and prevention of thrombosis due to their lower hemorrhagic effects. We investigate the recombinant kallikrein inhibitor (rBbKIm) containing the RGD/RGE motif and its related peptides in arterial thrombosis models. rBbKIm prolonged activated partial thromboplastin time by 3.5 (8.6 µM) and 4.1 times (17.2 µM), and extended the arterial occlusion time in a dose-dependent manner: 2.0 mg/kg (48.83 ± 15.87 min), 4.0 mg/kg (73.06 ± 21.38 min) and 8.0 mg/kg (94.13 ± 11.25 min) compared with control (0.15 M NaCl, 29.70 ± 7.14 min). Similar results were obtained with the RGD-peptide, 2.5 mg/kg (62.85 ± 18.53 min) and 5.0 mg/kg (89.50 ± 8.63 min). Thrombus sizes were decreased in the rBbKIm, RGD-peptide, and fondaparinux (0.7 mg/kg) treated groups, due to reduced adhesion of platelet to the endothelium. ADP-induced platelet aggregation ex vivo was inhibited by both rBbKIm (4.0 mg/kg, 75 %) and the RGD-peptide (5.0 mg/kg, 56 %), and they did not modify the bleeding time in contrast to fondaparinux. rBbKIm and RGD-related-peptide delayed the artery occlusion and reduced the thrombus size without any modification of the bleeding time, thereby impairing the aggregation and/or adhesion of platelets, making them useful for thrombosis therapy.
publishDate 2022
dc.date.none.fl_str_mv 2022-11-01
2023-03-01T21:09:15Z
2023-03-01T21:09:15Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1016/j.procbio.2022.08.013
Process Biochemistry, v. 122, p. 1-12.
1359-5113
http://hdl.handle.net/11449/241545
10.1016/j.procbio.2022.08.013
2-s2.0-85136497497
url http://dx.doi.org/10.1016/j.procbio.2022.08.013
http://hdl.handle.net/11449/241545
identifier_str_mv Process Biochemistry, v. 122, p. 1-12.
1359-5113
10.1016/j.procbio.2022.08.013
2-s2.0-85136497497
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Process Biochemistry
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 1-12
dc.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
repository.mail.fl_str_mv
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