Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

Capra, Valérie; Bäck, Magnus; Angiolillo, Dominick J.; Cattaneo, Marco; Sakariassen, Kjell S.

doi:10.1111/jth.12472

Cited by 78 publications

(54 citation statements)

References 110 publications

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“…This is because the distribution of antibodies to compartments other than the vascular is, in general, restricted because of poor penetration of the endothelial cell layer 61, 62, 63. Thus, these approaches may allow us to address bleeding time and thrombosis under conditions of selective modulation of the platelet TPRs, but not those TPRs of the smooth muscle64, 65, 66 (which are known to affect bleeding time). Strikingly perhaps, but as predicted, the C‐EL2–immunized mice possessed a tail bleeding time that was no different from the controls (C‐EL2r and KLH), indicating that it does not interfere with hemostasis.…”

Section: Discussionmentioning

confidence: 99%

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

Alshbool

Karim

Espinosa

et al. 2018

JAHA

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BackgroundDespite the well‐established role for the thromboxane A2 receptor (TPR) in the development of thrombotic disorders, none of the antagonists developed to date has been approved for clinical use. To this end, we have previously shown that an antibody targeted against TPR's ligand‐binding domain inhibits platelet activation and thrombus formation, without exerting any effects on hemostasis. Thus, the goal of the present studies is to design a novel TPR‐based vaccine, demonstrate its ability to trigger an immune response, and characterize its antiplatelet and antithrombotic activity.Methods and ResultsWe used a mouse keyhole limpet hemocyanin/peptide‐based vaccination approach rationalized over the TPR ligand‐binding domain (ie, the C‐terminus of the second extracellular loop). The biological activity of this vaccine was assessed in the context of platelets and thrombotic diseases, and using a host of in vitro and in vivo platelet function experiments. Our results revealed that the TPR C‐terminus of the second extracellular loop vaccine, in mice: (1) triggered an immune response, which resulted in the development of a C‐terminus of the second extracellular loop antibody; (2) did not affect expression of major platelet integrins (eg, glycoprotein IIb‐IIIa); (3) selectively inhibited TPR‐mediated platelet aggregation, platelet‐leukocyte aggregation, integrin glycoprotein IIb‐IIIa activation, as well as dense and α granule release; (4) significantly prolonged thrombus formation; and (5) did so without impairing physiological hemostasis.ConclusionsCollectively, our findings shed light on TPR's structural biological features, and demonstrate that the C‐terminus of the second extracellular loop domain may define a new therapeutic target and a TPR vaccine‐based approach that should have therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

Alshbool

Karim

Espinosa

et al. 2018

JAHA

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“…PGI 2 ) is not affected by TXS selective inhibitors as it is for inhibitor COX-1 42 . By keeping PGH levels unaltered through treatment with 3a, the activation of the TP receptor by PGH 2 or the production of natural platelet modulators such as PGI 2 or prostacyclin is maintained by both platelets, endothelial and inflammatory cells, which lead to improved hemostasis 60 .…”

Section: Discussionmentioning

confidence: 99%

“…However, animals that survived the induction of pulmonary thromboembolism through prior treatment with derivative 3a, showed reduction of thrombus size and thrombi deposition after five days, indicating that the mechanism of action of this derivative may ease fibrinolysis and clot removal over time, which may be related to the high survival rate observed for this molecule 41,42 . The lack of inhibition observed for U-44619-induced platelet aggregation suggests that the presence of the compounds does not influence the TP receptor activity, prompting that the inhibition of ARA-induced aggregation relies in the inhibition of upstream enzymes [43][44][45] .…”

Section: Discussionmentioning

confidence: 99%

“…Considering that pulmonary thromboembolism is not only dependent of vessel obstruction but also on bronchoconstriction and vasoconstriction events, the inhibition of prostaglandins production through active COX-1 inhibition decreases lung gas exchange and generates an increase in bleeding time [61][62][63] . TXS inhibitors in other hand, reverse these effects and offer a lower bleeding risk with improved oxygen perfusion 3,64 through improved vasodilation and bronchodilation, as well the formation of more soluble thrombi 41,42,63 . This unique characteristic may be the underlying reason for the improved survival rate observed for derivative 3a in comparison to ASA.…”

Section: Discussionmentioning

confidence: 99%

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Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

Saito

Lourenço

Dias

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N 0 -substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo [3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE 2 and TXB 2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.

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“…Interestingly, R122C P2Y 12 is the second platelet receptor described to share this behavior, the first one being the thromboxane prostanoid (TP) receptor, another class A GPCR coupled to several G proteins (promiscuous receptor), including G q [18]. The R130V mutant TP receptor was characterized by a significantly blunted agonist response, no increase in basal activity, loss of high affinity agonist binding and uncoupling from its cognate G protein [19].…”

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confidence: 99%

The DRY motif at work: the P2Y12 receptor case

Rovati¹,

Capra

2014

Journal of Thrombosis and Haemostasis

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A novel mutation in the P2Y 12 receptor and a function-reducing polymorphism in protease-activated receptor 1 in a patient with chronic bleeding. This issue, pp 716-25.Platelets play a central role not only in physiological hemostasis and repairing vascular damage, but also within the atherosclerotic process as well as in vascular occlusion and thrombosis, crucial events in myocardial infarction and stroke. They interact with activated endothelium, undergo chemotaxis, release adhesive proteins, vasoactive substances and pro-inflammatory mediators, activate other inflammatory cells, and exert phagocytosis [1]. Platelets express a wide range of receptors and proteins, and among them P2Y 1 and P2Y 12 , receptors for adenosine diphosphate (ADP), are necessary for platelet activation, aggregation and secretion [2]. In particular, the P2Y 12 receptor, a member of the rhodopsin family (class A, purine receptor cluster within the d group) of the G proteincoupled receptor (GPCR) gene superfamily, has attracted a significant amount of attention. In this issue of the Journal of Thrombosis and Haemostasis, Patel and colleagues have identified a patient with a lifelong history of chronic bleeding disorder expressing a homozygous P2RY12 gene mutation, resulting in an Arg to Cys substitution (R122C) in the P2Y 12 receptor sequence accompanied by a single nucleotide polymorphism (SNP) of the F2R gene encoding the PAR-1 receptor for thrombin. Because this latter intronic polymorphism has been previously associated with decreased receptor expression and reduced PAR-1 activity [3], it has not been studied further.Platelets from this patient (P1) showed lack of ADPand PAR-1-induced aggregation responses, as well as ADP-induced pVASP phosphorylation, whereas platelets from her two sons (P2 and P3), heterozygous for the same missense mutation in the P2R12 gene, showed a reduced response, particularly at low ADP concentrations. Interestingly, binding studies in platelets from these patients showed a decrease in affinity for the P2Y 12 agonist 2-MeSADP and in surface receptor expression compared with healthy donors (HD) [4]. Accordingly, in vitro studies with cells stably expressing the R122C receptor variant confirmed significantly impairment of receptor activity compared with WT P2Y 12 , when cells with similar levels of receptor expression were skillfully selected, and no increase in basal activity. These features point to a 'loss of function' receptor variant likely due to an impairment of G protein coupling.It is worth noticing here that the R122 of the P2Y 12 receptor, despite not being the only Arg associated with impairment of P2Y 12 receptor function [5], corresponds to the central Arg (i.e. R 3.50 , using Ballesteros notation) of the highly conserved Glu/Asp-Arg triplet located at the boundary between transmembrane domain (TM) III and intracellular loop (ICL) 2 of class A GPCRs, the so called E/DRY motif, that has been shown to be involved in GPCR activation and/or G protein coupling [6]. To date, only two other class A GPCRs...

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Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

Cited by 78 publications

References 110 publications

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

The DRY motif at work: the P2Y12 receptor case

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Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

Cited by 78 publications

References 110 publications

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

The DRY motif at work: the P2Y12 receptor case

Contact Info

Product

Resources

About

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis