Tuning the Thromboinflammatory Response to Venous Flow Interruption by the Ectonucleotidase CD39

Anyanwu, Anuli C.; Kanthi, Yogendra; Fukase, Keigo; Liao, Hui; Mimura, Tekashi; Desch, Karl C.; Gruca, Martin; Kaskar, Saabir; Sheikh-Aden, Hussein; Chi, Liguo; Zhao, Raymond; Yadav, Vinita; Wakefield, Thomas W.; Hyman, Matthew C.; Pinsky, David J.

doi:10.1161/atvbaha.119.312407

Cited by 20 publications

(19 citation statements)

References 68 publications

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“… 12 – 14 Acute inflammation was shown to drive the thrombosis in the animal models of arterial and venous thrombosis by multiple mechanisms, including increased expression of TF, CAMs, and chemokines. 15 , 16 The generation of thrombin further amplifies the endothelial damage and inflammation, which leads to vascular dysfunction. 17 , 18 Therefore, thromboinflammatory stress is considered a crucial event in the pathogenesis of thrombosis associated with inflammatory diseases.…”

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confidence: 99%

Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction

Kondreddy

Magisetty

Keshava

et al. 2021

ATVB

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Objective: In response to inflammatory insult, endothelial cells express cell adhesion molecules and TF (tissue factor), leading to increased adhesion of leukocytes to the endothelium and activation of coagulation. Enhanced coagulation could further exacerbate inflammation. Identifying key signaling molecule(s) that drive both inflammation and coagulation may help devise effective therapeutic strategies to treat inflammatory and thrombotic disorders. The aim of the current study to determine the role of Gab2 (Grb2-associated binder2), which is known to play a crucial role in the signaling evoked by growth factors and antigen receptors, in inflammatory signaling pathways and contributing to vascular dysfunction. Approach and Results: WT (wild type) and Gab2-silenced endothelial cells were treated with TNFα (tumor necrosis factor alpha), IL (interleukin)-1β, or lipopolysaccharide (LPS). Activation of key signaling proteins in the inflammatory signaling pathways and expression of cell adhesion molecules, TF, and inflammatory cytokines were analyzed. Gab2 −/ − and WT littermate mice were challenged with LPS or S pneumoniae , and parameters of inflammation and activation of coagulation were assessed. Gab2 silencing in endothelial cells markedly attenuated TNFα-induced, IL-1β–induced, and LPS-induced expression of TF, cell adhesion molecules, and inflammatory cytokines/chemokines. Gab2 silencing suppressed TNFα-induced, IL-1β–induced, and LPS-induced phosphorylation and ubiquitination of TAK1 and activation of MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor kappa B). Immunoprecipitation studies revealed that the Src kinase Fyn phosphorylates Gab2. Gab2 −/− mice are protected from LPS or S pneumoniae –induced vascular permeability, neutrophil infiltration, thrombin generation, NET formation, cytokine production, and lung injury. Conclusions: Our studies identify, for the first time, that Gab2 integrates signaling from multiple inflammatory receptors and regulates vascular inflammation and thrombosis.

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confidence: 99%

Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction

Kondreddy

Magisetty

Keshava

et al. 2021

ATVB

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“…The importance of this enzymatic action is in the effects of ADP in the P2Y12 receptor, which is metabotropic and is present in platelets. The function of P2Y12 is monocytic activation and platelet aggregation through the activity of thrombin, collagen, and thromboxane A2 [ 11 , 40 , 41 ]. There are drugs developed that selectively inhibit P2Y12 and that are already commercialized with an indication for some cardiovascular diseases, for example, clopidogrel [ 42 , 43 ].…”

Section: Thrombosis and P2y12r In Covid-19mentioning

confidence: 99%

Possible role of purinergic signaling in COVID-19

et al. 2021

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The coronavirus disease (COVID-19), caused by SARS-CoV-2 infection, accounts for more than 2.4 million deaths worldwide, making it the main public health problem in 2020. Purinergic signaling is involved in the pathophysiology of several viral infections which makes the purinergic system a potential target of investigation in COVID-19. During viral infections, the ATP release initiates a cascade that activates purinergic receptors. This receptor activation enhances the secretion of pro-inflammatory cytokines and performs the chemotaxis of macrophages and neutrophils, generating an association between the immune and the purinergic systems. This review was designed to cover the possible functions of purinergic signaling in COVID-19, focusing on the possible role of purinergic receptors such as P2X7 which contributes to cytokine storm and inflammasome NLRP3 activation and P2Y1 that activates the blood coagulation pathway. The possible role of ectonucleotidases, such as CD39 and CD73, which have the function of dephosphorylating ATP in an immunosuppressive component, adenosine, are also covered in detail. Moreover, therapeutic combination or association possibilities targeting purinergic system components are also suggested as a possible useful tool to be tested in future researches, aiming to unveil a novel option to treat COVID-19 patients.

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“…Interestingly, the authors demonstrate that CD39 deficiency increases neutrophil activation and NET formation. Increased circulating platelet/neutrophil hetero-aggregates have been found in CD39-null mice [ 8 , 87 ]. Such findings demonstrate that CD39 is crucial to mitigate the thrombo-inflammatory response under reduced blood flow conditions [ 8 , 87 ].…”

Section: Ntpdase1/cd39 Bridging Inflammation and Thrombosismentioning

confidence: 99%

Thrombo-Inflammation: A Focus on NTPDase1/CD39

Morello

Caiazzo

Turiello

et al. 2021

Cells

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There is increasing evidence for a link between inflammation and thrombosis. Following tissue injury, vascular endothelium becomes activated, losing its antithrombotic properties whereas inflammatory mediators build up a prothrombotic environment. Platelets are the first elements to be activated following endothelial damage; they participate in physiological haemostasis, but also in inflammatory and thrombotic events occurring in an injured tissue. While physiological haemostasis develops rapidly to prevent excessive blood loss in the endothelium activated by inflammation, hypoxia or by altered blood flow, thrombosis develops slowly. Activated platelets release the content of their granules, including ATP and ADP released from their dense granules. Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 dephosphorylates ATP to ADP and to AMP, which in turn, is hydrolysed to adenosine by ecto-5′-nucleotidase (CD73). NTPDase1/CD39 has emerged has an important molecule in the vasculature and on platelet surfaces; it limits thrombotic events and contributes to maintain the antithrombotic properties of endothelium. The aim of the present review is to provide an overview of platelets as cellular elements interfacing haemostasis and inflammation, with a particular focus on the emerging role of NTPDase1/CD39 in controlling both processes.

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Tuning the Thromboinflammatory Response to Venous Flow Interruption by the Ectonucleotidase CD39

Cited by 20 publications

References 68 publications

Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction

Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction

Possible role of purinergic signaling in COVID-19

Thrombo-Inflammation: A Focus on NTPDase1/CD39

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