Abstract
Snake venom contains large amounts of active proteins and peptides. In this study, a novel snake protein, metalloproteinase SP, was successfully isolated from the venom of Agkistrodon acutus by multi-gel chromatography. The isolated protein exhibits anti-platelet aggregation activity. Animal experiments showed that it exhibited defibration, anticoagulation, and antithrombotic effects and contributes to improved blood rheology and antiplatelet aggregation. In vivo experiments demonstrated that it prolonged clotting time, partial thromboplastin time, prothrombin time, thrombin time, fibrinogen time and reduced fibrinogen content of mice. Also, metalloproteinase SP inhibited carrageenan-induced tail thrombosis, ADP-induced acute pulmonary embolism, and ADP, Arachidonic acid (AA), or collagen-induced platelet aggregation. In vitro experiments showed that the protein cleaved the α, β, and γ chains of fibrinogen. Metabolomic analysis upon metalloproteinase SP treatment revealed that 14 metabolites, which are mainly involved in phenylalanine, tyrosine, and tryptophan biosynthesis, responded to metalloproteinase SP treatment. In summary, the isolated snake venom protein inhibits formation of acute pulmonary embolism probably through regulating and restoring perturbed energy, lipid, and amino acid metabolism.
Highlights
Thrombotic disease is one with a high morbidity and mortality rate in the world, accounting for approximately 40% of deaths yearly [1]
In order to study the mechanism of action of the novel snake venom protein, we investigated its antithrombotic effect using fibrinogen solubilization assay combined with UPLC-Q/TOF-MS-based non-targeted plasma metabolomics
Based on LC-MS/MS analysis and database search analysis, it was found that three specific amino acid sequence fragments including SFGEWR, STEFQR, ENPPCILNKP were identified to belong to metalloproteinase SP (Figure 1D and Figure S1)
Summary
Thrombotic disease is one with a high morbidity and mortality rate in the world, accounting for approximately 40% of deaths yearly [1]. The formation of thrombus is closely related to platelet aggregation, blood coagulation, and fibrin network formation. Antithrombotic drugs are categorized into three groups: anti-platelet aggregation drugs, anticoagulants, and thrombolytic drugs. Evidence from recent research indicates that snake venom contains many active protein or peptides with defibration, anticoagulation, antiplatelet aggregation, and antithrombotic functions [4]. The anti-thrombotic action of snake venom protein is due to its ability to cleave the fibrinogen, reduce the content of fibrinogen, activate fibrinolytic enzyme, inhibit the activation of FXa, FIIa, thrombin, and other coagulation factors [5,6,7]. A large number of snake venom protease components have been isolated and some snake venom preparations are widely used in clinical practice
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