Coagulation signalling following tissue injury: Focus on the role of factor Xa

Krupiczojc, Malvina A.; Scotton, Chris J.; Chambers, Rachel C.

doi:10.1016/j.biocel.2008.02.026

Cited by 54 publications

(48 citation statements)

References 83 publications

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“…Because FXa induces inflammation, 12,13 we tested whether FXa inhibitor changes the expression levels of proinflammatory and profibrotic genes (Tgfb, Pai1, Col1, Col4, and Tnfa). As expected, the expression of these genes was upregulated in the kidneys of the eNOS −/− DM mice ( Figure 3A; Table II in the online-only Data Supplement).…”

Section: Inhibition Of Fxa Corrects Expression Of Inflammatory/fibrotmentioning

confidence: 99%

“…[12][13][14] Inflammation plays a pivotal role in the progression of DN. [21][22][23][24] We therefore investigated whether FXa and PAR2 activation directly cause inflammation in endothelial cells and podocytes in vitro.…”

Section: Fxa and Par2 Agonist Exacerbate Inflammation In Endothelial mentioning

confidence: 99%

“…PAR2 is activated by TF-coagulation factor VIIa complex and coagulation factor Xa (FXa) and upregulates inflammation and fibrosis through nuclear factor-kappa B (NF-κB) or mitogenactivated protein kinase (MAPK) signaling. [12][13][14] Although FXa and PAR2 are suggested to be responsible for the progression of kidney injury, [15][16][17][18] their role in DN is poorly understood.…”

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confidence: 99%

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Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy

Hayashi

Fushima

et al. 2016

ATVB

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Objective-The role of hypercoagulability in the pathogenesis of diabetic nephropathy (DN) remains elusive. We recently reported the increased infiltration of macrophages expressing tissue factor in diabetic kidney glomeruli; tissue factor activates coagulation factor X (FX) to FXa, which in turn stimulates protease-activated receptor 2 (PAR2) and causes inflammation. Approach and Results-Here, we demonstrated that diabetes mellitus increased renal FX mRNA, urinary FXa activity, and FX expression in glomerular macrophages. Administration of an oral FXa inhibitor, edoxaban, ameliorated DN with concomitant reductions in the expression of PARs (Par1 and Par2) and of proinflammatory and profibrotic genes. Diabetes mellitus induced PAR2, and lack of Par2 ameliorated DN. FXa or PAR2 agonist increased inflammatory cytokines in endothelial cells and podocytes in vitro. Conclusions-We conclude that enhanced FXa and PAR2 exacerbate DN and that both are promising targets for preventing DN. Alleviating inflammation is probably more important than inhibiting coagulation per se when treating kidney diseases using anticoagulants.

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Section: Inhibition Of Fxa Corrects Expression Of Inflammatory/fibrotmentioning

confidence: 99%

Section: Fxa and Par2 Agonist Exacerbate Inflammation In Endothelial mentioning

confidence: 99%

mentioning

confidence: 99%

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Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy

Hayashi

Fushima

et al. 2016

ATVB

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“…25 Thrombin at low concentrations may enhance endothelial barrier function, but at higher doses, it increases endothelial permeability, the latter being a feature of inflammation. 26 In a similar manner to thrombin, factor Xa exhibits a wide range of proinflammatory properties (reviewed in Krupiczojc et al 27 ). Moreover, generation of factor Xa may be facilitated by pathogens, such as viruses 28 or immune cells, without requiring TF.…”

Section: Thrombin Factor Xa and The Protease-activated Receptorsmentioning

confidence: 99%

Coagulation and innate immune responses: can we view them separately?

Delvaeye

Conway

2009

Blood

265

210

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The horseshoe crab is often referred to as a "living fossil," representative of the oldest classes of arthropods, almost identical to species in existence more than 500 million years ago. Comparative analyses of the defense mechanisms used by the horseshoe crab that allowed it to survive mostly unchanged throughout the millennia reveal a common ancestry of the coagulation and innate immune systems that are totally integrated-indeed, almost inseparable. In human biology, we traditionally view the hemostatic pathways and those regulating innate immune responses to infections and tissue damage as entirely separate entities. But are they? The last couple of decades have revealed a remarkable degree of interplay between these systems, and the linking cellular and molecular mechanisms are rapidly being delineated. In this review, we present some of the major points of intersection between coagulation and innate immunity. We attempt to highlight the potential impact of these findings by identifying recently established paradigms that will hopefully result in the emergence of new strategies to treat a range of inflammatory and hemostatic disorders. IntroductionThe most menacing challenge to survival that is faced by organisms throughout the animal kingdom is invasion by infections and foreign antigens-events that are frequently accompanied by trauma or a wound. Organisms have thus necessarily developed a variety of effective means to restrict and to fight infections, to contain wounds by limiting bleeding with clot formation, and to rapidly initiate healing. The coexistence of thrombosis with inflammatory responses supports the notion that common molecular mechanisms regulate these complex biologic systems. The last couple of decades have seen major progress in identifying cellular and molecular links between these systems.In this review, we consider some of the key pathways involved in hemostasis, innate immunity, and inflammation, and provide recent data that demonstrate how they are integrated. The interactions are multiple and complex, and present new challenges to identify those that are clinically relevant, with the promise of discovering novel and more effective therapies for a range of diseases. CoagulationThe coagulation system is characterized by the sequential, rapid, and highly localized activation of a series of serine proteases, culminating in the generation of thrombin, with subsequent conversion of fibrinogen into a fibrin clot. Tissue factor (TF) is the key initiator of coagulation (reviewed in Mackman 1 ), and is expressed primarily by subendothelial mural cells and adventitial fibroblasts in and around the vessel wall. Somewhat controversial, it may also be expressed at low levels by monocytes and neutrophils, and found circulating in microparticles and in a soluble form. 2 With vascular endothelial cell damage, TF is exposed to the circulation, and complexes with factor VII/VIIa, initiating activation of factors IX and X. Factor Xa converts prothrombin to thrombin in sufficient quantities to activat...

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“…7 Indeed, FX has been linked to fibroproliferative diseases, including tissue remodeling, fibrosis, cancer, and inflammation particularly after tissue injury in different pathologies. 8,9 The mechanism by which FX modulates these processes is incompletely understood but seems to be related to the capacity of FXa to induce signaling pathways via the proteinase-activated receptors 1 and 2 (PAR-1 and -2). Another biological process involving FX concerns viral infections through its binding to the surface of herpes simplex virus-1 or human species C adenovirus.…”

Section: Introductionmentioning

confidence: 99%

Macrophage receptor SR-AI is crucial to maintain normal plasma levels of coagulation factor X

Muczynski

Bazaa

Loubière

et al. 2016

Blood

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Key Points• SR-AI is the major receptor of FX at the macrophage surface.• Macrophages use SR-AI to control FX circulatory levels.Beside its classical role in the coagulation cascade, coagulation factor X (FX) is involved in several major biological processes including inflammation and enhancement of virusinduced immune responses. We recently reported that the long circulatory half-life of FX is linked to its interaction with liver-resident macrophages. Importantly, we now observed that macrophages, but not undifferentiated monocytes, support this interaction. Using cell biology approaches with primary and THP1-derived macrophages as well as transfected cells, we further identified the scavenger receptor type A member I (SR-AI) to be a macrophage-specific receptor for FX. This result was confirmed using SR-AI-deficient mice, which exhibit reduced circulating levels of FX in vivo and loss of FX-macrophage interactions in vitro. Binding studies using purified proteins revealed that FX binds specifically (half-maximal binding, 3 mg/mL) to the extracellular domain of SR-AI. Altogether, we demonstrate that macrophages regulate FX plasma levels in an SR-AI-dependent manner. (Blood. 2016;127(6):778-786)

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Coagulation signalling following tissue injury: Focus on the role of factor Xa

Cited by 54 publications

References 83 publications

Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy

Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy

Coagulation and innate immune responses: can we view them separately?

Macrophage receptor SR-AI is crucial to maintain normal plasma levels of coagulation factor X

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