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Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [20-0174 RNA-seq]

ABSTRACT: While thrombin is the key protease in regard to thrombus formation, other coagulation proteases, such as fXa or activated protein C (aPC), independently modulate intracellular signaling via partially disjunct receptors. Hence, we postulate that inhibition of fXa or fIIa conveys different effects in myocardial ischemia-reperfusion injury (IRI) in regard to inflammation despite comparable anticoagulant efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE161324 | GEO | 2021/07/28

REPOSITORIES: GEO

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Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury [19-0267 RNA-seq]

Project description:While thrombin is the key protease in regard to thrombus formation, other coagulation proteases, such as fXa or activated protein C (aPC), independently modulate intracellular signaling via partially disjunct receptors. Hence, we postulate that inhibition of fXa or fIIa conveys different effects in myocardial ischemia-reperfusion injury (IRI) in regard to inflammation despite comparable anticoagulant efficacy.

2021-07-28 | GSE161323 | GEO

Theoretical Study of Molecular Structure and Physicochemical Properties of Novel Factor Xa Inhibitors and Dual Factor Xa and Factor IIa Inhibitors.

Project description:The geometries and energies of factor Xa inhibitors edoxaban, eribaxaban, fidexaban, darexaban, letaxaban, and the dual factor Xa and thrombin inhibitors tanogitran and SAR107375 in both the gas-phase and aqueous solution were studied using the Becke3LYP/6-31++G(d,p) or Grimme's B97D/6-31++G(d,p) method. The fully optimized conformers of these anticoagulants show a characteristic l-shape structure, and the water had a remarkable effect on the equilibrium geometry. According to the calculated pKa values eribaxaban and letaxaban are in neutral undissociated form at pH 7.4, while fidexaban and tanogitran exist as zwitterionic structures. The lipophilicity of the inhibitors studied lies within a large range of log P between 1 and 4. The dual inhibitor SAR107375 represents an improvement in structural, physicochemical and pharmacokinetic characteristics over tanogitran. At blood pH, SAR107375 predominantly exists in neutral form. In contrast with tanogitran, it is better absorbed and more lipophilic and active after oral application.

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Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-07-28 | GSE161325 | GEO

Chemoenzymatic synthesis of heparin oligosaccharides with both anti-factor Xa and anti-factor IIa activities.

Project description:Heparan sulfate (HS) and heparin are highly sulfated polysaccharides. Heparin is a commonly used anticoagulant drug that inhibits the activities of factors Xa and IIa (also known as thrombin) to prevent blood clot formation. Here, we report the synthesis of a series of size-defined oligosaccharides to probe the minimum size requirement for an oligosaccharide with anti-IIa activity. The synthesis was completed by a chemoenzymatic approach involving glycosyltransferases, HS sulfotransferases, and C(5)-epimerase. We demonstrate the ability to synthesize highly purified N-sulfo-oligosaccharides having up to 21 saccharide residues. The results from anti-Xa and anti-IIa activity measurements revealed that an oligosaccharide longer than 19 saccharide residues is necessary to display anti-IIa activity. The oligosaccharides also exhibit low binding toward platelet factor 4, raising the possibility of preparing a synthetic heparin with a reduced effect of heparin-induced thrombocytopenia. The results from this study demonstrate the ability to synthesize large HS oligosaccharides and provide a unique tool to probe the structure and function relationships of HS that require the use of large HS fragments.

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Parenteral administration of factor Xa/IIa inhibitors limits experimental aortic aneurysm and atherosclerosis.

Project description:Intraluminal thrombus is a consistent feature of human abdominal aortic aneurysm (AAA). Coagulation factor Xa (FXa) catalyses FII to thrombin (FIIa). We examined the effect of FXa/FIIa inhibition on experimental aortic aneurysm in apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII). The concentration of FXa within the supra-renal aorta (SRA) correlated positively with SRA diameter. Parenteral administration of enoxaparin (FXa/IIa inhibitor) and fondaparinux (FXa inhibitor) over 14 days reduced to severity of aortic aneurysm and atherosclerosis in AngII-infused ApoE-/- mice. Enteral administration of the FIIa inhibitor dabigatran had no significant effect. Aortic protease-activated receptor (PAR)-2 expression increased in response to AngII infusion. Fondaparinux reduced SRA levels of FXa, FIIa, PAR-2, matrix metalloproteinase (MMP)2, Smad2/3 phosphorylation, and MOMA-2 positive cells in the mouse model. FXa stimulated Smad2/3 phosphorylation and MMP2 expression in aortic vascular smooth muscle cells (VSMC) in vitro. Expression of MMP2 in FXa-stimulated VSMC was downregulated in the presence of a PAR-2 but not a PAR-1 inhibitor. These findings suggest that FXa/FIIa inhibition limits aortic aneurysm and atherosclerosis severity due to down-regulation of vascular PAR-2-mediated Smad2/3 signalling and MMP2 expression. Inhibition of FXa/FIIa may be a potential therapy for limiting aortic aneurysm.

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Antithrombotics and new interventions for venous thromboembolism: Exploring possibilities beyond factor IIa and factor Xa inhibition.

Project description:Direct oral anti-activated factor X and antithrombin agents have largely replaced vitamin K antagonists as the standard of care in treatment of venous thromboembolism. However, gaps in efficacy and safety persist, notably in end-stage renal disease, implantable heart valves or assist devices, extracorporeal support of the circulation, and antiphospholipid syndrome. Inhibition of coagulation factor XI (FXI) emerges as a promising new therapeutic target. Antisense oligonucleotides offer potential advantages as a prophylactic or therapeutic modality, with one dose-finding trial in orthopedic surgery already published. In addition, monoclonal antibodies blocking activation and/or activity of activated factor XI are investigated, as are small-molecule inhibitors with rapid offset of action. Further potential targets include upstream components of the contact pathway such as factor XII, polyphosphates, or kallikrein. Finally, catheter-directed, pharmacomechanical antithrombotic strategies have been developed for high- and intermediate-risk pulmonary embolism, and large randomized trials aiming to validate their efficacy, safety, and prognostic impact are about to start.

| S-EPMC8130658 | biostudies-literature

Self-anticoagulant sponges for whole blood auto-transfusion and its mechanism of coagulation factor inactivation

Project description:Clinical use of intraoperative auto-transfusion requires the removal of platelets and plasma proteins due to the pump-based suction and water-soluble anticoagulant administration, which causes dilutional coagulopathy. Herein, we develop a carboxylated and sulfonated heparin-mimetic polymer-modified sponge that could spontaneously adsorb blood (1.149 kg/m-2 s-1/2) along with instantaneous anticoagulation. We demonstrate that intrinsic coagulation factors (especially XI) are inactivated by adsorption to the sponge surface, while inactivation of thrombin in the sponge-treated plasma effectively inhibits the common coagulation pathway. Benefiting from the multiple inhibitory effects of sponge on coagulation enzymes and calcium depletion, the whole blood auto-transfusion in trauma-induced hemorrhage is unprecedentedly realized. The transfusion of collected blood favors faster recovery of hemostasis compared to traditional heparinized blood in an animal model. Our work not only develops a safe and convenient approach for whole blood auto-transfusion, but also provides the mechanism of action of self-anticoagulant heparin-mimetic polymer-modified surfaces.

2023-07-23 | PXD044005 | Pride

Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis with no increased bleeding risk

Project description:Atrial fibrillation (AF) is a major risk factor for cardioembolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern particularly when antiplatelet treatment is simultaneously administered. Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke identified a stroke related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was downregulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out (KO) mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. In WT mice, Hsp70 inducers (TRC051384, or tubastatin A) delayed thrombus formation. Remarkably, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression, higher circulating levels of activated protein C (APC) upon thrombotic stimulus and increased protection against endothelial apoptosis. Thus, Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, being especially promising in situations where there is a major bleeding hazard. Microarray analysis in peripheral blood cells includes eight patients with AF and stroke and eight AF subjects without stroke

2016-04-01 | E-GEOD-66724 | biostudies-arrayexpress

Coagulation Factor Xa

Project description:The third edition of the Handbook of Proteolytic Enzymes aims to be a comprehensive reference work for the enzymes that cleave proteins and peptides, and contains over 800 chapters. Each chapter is organized into sections describing the name and history, activity and specificity, structural chemistry, preparation, biological aspects, and distinguishing features for a specific peptidase. The subject of Chapter 642 is Coagulation Factor Xa. Keywords Coagulation factor, prothrombin, thrombin, proconvertin, Stuart’s factor, Prower’s factor.

| S-EPMC7149769 | biostudies-literature

Adipose-derived mesenchymal stem cells overexpressing thrombomodulin reduce thrombogenic risk and enhance therapeutic efficacy

Project description:Adipose-derived mesenchymal stem cells (ASCs) are expected to be a new therapy to prevent progression of renal fibrosis; however, they were reported to have procoagulant activity, raising concerns about thrombogenic risk. Thrombomodulin (TM) acts as an anticoagulant factor by binding to thrombin, leading to the hypothesis that ASCs overexpressing TM (TM-ASCs) could be safely used for cell therapy by reducing the risk of thromboembolism. Overexpression of TM using adeno-associated virus (AAV) reduced rat deaths related to renal infarction and pulmonary embolism induced by ASCs. Interestingly, TM-ASCs alleviated renal inflammation and fibrosis potently in ischemia-reperfusion injury (IRI) rats. The therapeutic mechanism of TM-ASCs involved increased prostaglandin E2 (PGE2) secretion, a shift in the macrophage phenotype to immunosuppressive M2 in vitro, and potent M2 macrophage polarization in the damaged areas in vivo. We produced ASCs with enhanced TM expression by pretreatment with a selective inhibitory kappa-B kinase-β (IKKβ) inhibitor. These ASCs also improved thrombotic mortality and markedly attenuated renal fibrosis induced by IRI, similar to TM-ASCs generated by AAV. ASCs with enhanced TM expression by IKKβ also increased PGE2 secretion, leading to a more pronounced polarization of M2 macrophages. Taken together, ASCs with enhanced TM expression eliminated the risk of thrombosis and reinforced therapeutic efficacy. These ASCs might become a standard cellular therapy for renal fibrosis via the intravascular injection of mesenchymal stem cells in the future.

2024-09-24 | GSE277567 | GEO

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