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Salivary Thromboxane A2-Binding Proteins from Triatomine Vectors of Chagas Disease Inhibit Platelet-Mediated Neutrophil Extracellular Traps (NETs) Formation and Arterial Thrombosis.

Mizurini DM, Aslan JS, Gomes T, Ma D, Francischetti IM, Monteiro RQ - PLoS Negl Trop Dis (2015)

Bottom Line: Effective antithrombotic doses of dipetalodipin and triplatin did not increase blood loss, which was estimated using the tail transection method.This ability may contribute to the antithrombotic effects in vivo.Our results provide new insight into the antihemostatic effects of TXA2-binding proteins and may have important significance in elucidating the mechanisms of saliva to avoid host's hemostatic responses and innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

ABSTRACT

Background: The saliva of blood-feeding arthropods contains a notable diversity of molecules that target the hemostatic and immune systems of the host. Dipetalodipin and triplatin are triatomine salivary proteins that exhibit high affinity binding to prostanoids, such as TXA2, thus resulting in potent inhibitory effect on platelet aggregation in vitro. It was recently demonstrated that platelet-derived TXA2 mediates the formation of neutrophil extracellular traps (NETs), a newly recognized link between inflammation and thrombosis that promote thrombus growth and stability.

Methodology/principal findings: This study evaluated the ability of dipetalodipin and triplatin to block NETs formation in vitro. We also investigated the in vivo antithrombotic activity of TXA2 binding proteins by employing two murine models of experimental thrombosis. Remarkably, we observed that both inhibitors abolished the platelet-mediated formation of NETs in vitro. Dipetalodipin and triplatin significantly increased carotid artery occlusion time in a FeCl3-induced injury model. Treatment with TXA2-binding proteins also protected mice from lethal pulmonary thromboembolism evoked by the intravenous injection of collagen and epinephrine. Effective antithrombotic doses of dipetalodipin and triplatin did not increase blood loss, which was estimated using the tail transection method.

Conclusions/significance: Salivary TXA2-binding proteins, dipetalodipin and triplatin, are capable to prevent platelet-mediated NETs formation in vitro. This ability may contribute to the antithrombotic effects in vivo. Notably, both molecules inhibit arterial thrombosis without promoting excessive bleeding. Our results provide new insight into the antihemostatic effects of TXA2-binding proteins and may have important significance in elucidating the mechanisms of saliva to avoid host's hemostatic responses and innate immune system.

No MeSH data available.


Related in: MedlinePlus

Effect of dipetalodipin and triplatin on the pulmonary embolism model.(A-B) Kaplan-Meier survival curves. Mortality associated with i.v. injection of collagen (0.8 mg/kg) and epinephrine (60 μg/kg) after administration of PBS, (A) dipetalodipin or (B) triplatin. Animals still alive 30 min after the challenge were considered survivors. **P < 0.01 vs control (log-rank test).
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pntd.0003869.g004: Effect of dipetalodipin and triplatin on the pulmonary embolism model.(A-B) Kaplan-Meier survival curves. Mortality associated with i.v. injection of collagen (0.8 mg/kg) and epinephrine (60 μg/kg) after administration of PBS, (A) dipetalodipin or (B) triplatin. Animals still alive 30 min after the challenge were considered survivors. **P < 0.01 vs control (log-rank test).

Mentions: The efficacy of dipetalodipin and triplatin in inhibiting thrombus formation was further measured in a murine model of lethal pulmonary thromboembolism, induced by intravenous infusion of collagen and epinephrine. All of the mice treated with vehicle (PBS, 10 out of 10) died within 5 min of collagen/epinephrine infusion (Fig 4). In contrast, the two groups of dipetalodipin—treated mice were significantly protected from death, with up to 50% of the mice surviving the challenge at the highest dose (2.0 mg/kg) (Fig 4A). When triplatin was administered prior to the collagen/epinephrine infusion, we observed a dose-dependent increase in the survival percentage (30% at 0.5 mg/kg and 60% at 2.0 mg/kg triplatin) (Fig 4B). Analysis of the histological sections of the lung tissues confirmed the presence of massive pulmonary thrombosis in PBS-treated mice, compared with the control mice or animals that were treated with either dipetalodipin or triplatin prior to the collagen/epinephrine challenge (S2 Fig).


Salivary Thromboxane A2-Binding Proteins from Triatomine Vectors of Chagas Disease Inhibit Platelet-Mediated Neutrophil Extracellular Traps (NETs) Formation and Arterial Thrombosis.

Mizurini DM, Aslan JS, Gomes T, Ma D, Francischetti IM, Monteiro RQ - PLoS Negl Trop Dis (2015)

Effect of dipetalodipin and triplatin on the pulmonary embolism model.(A-B) Kaplan-Meier survival curves. Mortality associated with i.v. injection of collagen (0.8 mg/kg) and epinephrine (60 μg/kg) after administration of PBS, (A) dipetalodipin or (B) triplatin. Animals still alive 30 min after the challenge were considered survivors. **P < 0.01 vs control (log-rank test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482233&req=5

pntd.0003869.g004: Effect of dipetalodipin and triplatin on the pulmonary embolism model.(A-B) Kaplan-Meier survival curves. Mortality associated with i.v. injection of collagen (0.8 mg/kg) and epinephrine (60 μg/kg) after administration of PBS, (A) dipetalodipin or (B) triplatin. Animals still alive 30 min after the challenge were considered survivors. **P < 0.01 vs control (log-rank test).
Mentions: The efficacy of dipetalodipin and triplatin in inhibiting thrombus formation was further measured in a murine model of lethal pulmonary thromboembolism, induced by intravenous infusion of collagen and epinephrine. All of the mice treated with vehicle (PBS, 10 out of 10) died within 5 min of collagen/epinephrine infusion (Fig 4). In contrast, the two groups of dipetalodipin—treated mice were significantly protected from death, with up to 50% of the mice surviving the challenge at the highest dose (2.0 mg/kg) (Fig 4A). When triplatin was administered prior to the collagen/epinephrine infusion, we observed a dose-dependent increase in the survival percentage (30% at 0.5 mg/kg and 60% at 2.0 mg/kg triplatin) (Fig 4B). Analysis of the histological sections of the lung tissues confirmed the presence of massive pulmonary thrombosis in PBS-treated mice, compared with the control mice or animals that were treated with either dipetalodipin or triplatin prior to the collagen/epinephrine challenge (S2 Fig).

Bottom Line: Effective antithrombotic doses of dipetalodipin and triplatin did not increase blood loss, which was estimated using the tail transection method.This ability may contribute to the antithrombotic effects in vivo.Our results provide new insight into the antihemostatic effects of TXA2-binding proteins and may have important significance in elucidating the mechanisms of saliva to avoid host's hemostatic responses and innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

ABSTRACT

Background: The saliva of blood-feeding arthropods contains a notable diversity of molecules that target the hemostatic and immune systems of the host. Dipetalodipin and triplatin are triatomine salivary proteins that exhibit high affinity binding to prostanoids, such as TXA2, thus resulting in potent inhibitory effect on platelet aggregation in vitro. It was recently demonstrated that platelet-derived TXA2 mediates the formation of neutrophil extracellular traps (NETs), a newly recognized link between inflammation and thrombosis that promote thrombus growth and stability.

Methodology/principal findings: This study evaluated the ability of dipetalodipin and triplatin to block NETs formation in vitro. We also investigated the in vivo antithrombotic activity of TXA2 binding proteins by employing two murine models of experimental thrombosis. Remarkably, we observed that both inhibitors abolished the platelet-mediated formation of NETs in vitro. Dipetalodipin and triplatin significantly increased carotid artery occlusion time in a FeCl3-induced injury model. Treatment with TXA2-binding proteins also protected mice from lethal pulmonary thromboembolism evoked by the intravenous injection of collagen and epinephrine. Effective antithrombotic doses of dipetalodipin and triplatin did not increase blood loss, which was estimated using the tail transection method.

Conclusions/significance: Salivary TXA2-binding proteins, dipetalodipin and triplatin, are capable to prevent platelet-mediated NETs formation in vitro. This ability may contribute to the antithrombotic effects in vivo. Notably, both molecules inhibit arterial thrombosis without promoting excessive bleeding. Our results provide new insight into the antihemostatic effects of TXA2-binding proteins and may have important significance in elucidating the mechanisms of saliva to avoid host's hemostatic responses and innate immune system.

No MeSH data available.


Related in: MedlinePlus