The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies. (November 2022)

• Record Type: Journal Article
• Authors: Medina, A.F.; Salu, B.R.; de Brito, M.V.; Bonturi, C.R.; Meneghetti, M.C.Z.; Maffei, F.H.A.; Oliva, M.L.V.
• Is Part Of: Process biochemistry. Volume 122(2022)Supplement Part 1
• Page Start: 1
• Page End: 12
• Publication Date: 2022-11
• Subjects: vWF von Willebrand factor -- TF tissue factor -- PKa kallikrein -- HK high molecular weight kininogen -- LK low molecular weight kininogen -- BbKI Bauhinia bauhinioides kallikrein inhibitor -- rBbKIm recombinant Bauhinia bauhinioides kallikrein inhibitor modified -- BrTI Bauhinia rufa trypsin inhibitor -- PRP platelet-rich plasma -- LC-ESI-MS Liquid Chromatography-Electrospray Ionization-Mass Spectrometry -- RGD-pep (acetyl-Y-L-E-P-V-A-R-G-D-G-G-L-A-amide) -- Ri-DGR-pep (acetyl-A-L-G-G-D-G-R-A-V-P-E-L-Y-amide) -- MAPK p38 mitogen-activated protein kinase -- AKT serine-threonine kinase -- ERK extracellular signal‐regulated kinase -- PAR-1 protease-activated receptor-1 -- Sirt1 factor sirtuin-1 -- KLF4 Kruppel-like factor 4 -- AT2R angiotensin 2 receptor -- tPA tissue plasminogen activator; Arterial thrombosis -- Blood coagulation -- Integrin -- Kallikrein -- Platelets; Biochemical engineering -- Periodicals; Biotechnology -- Periodicals; Biochemistry -- periodicals; Biotechnology -- periodicals; Chemical Engineering -- periodicals; Génie biochimique -- Périodiques; Biotechnologie -- Périodiques; Biochemical engineering; Biotechnology; Periodicals; 660.63
• DOI: 10.1016/j.procbio.2022.08.013
• Languages: English
• ISSNs: 1359-5113

Abstract

Abstract: 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. Graphical Abstract: ga1 Highlights: PKa blockade may be a new target in antithrombotic therapies. The RGD sequence in PKa inhibitor is important for its specific antithrombotic action. Plasma kallikrein is a target to be explored in antithrombotic therapies. Inhibitors containing RGD interfere with platelet aggregation, preventing thrombosis