P2Y12 receptor antagonists and AR receptor agonists regulates Protein Disulfide Isomerase secretion from platelets and endothelial cells

Popielarski, Marcin; Ponamarczuk, Halszka; Stasiak, Marta; Gdula, Anna M.; Bednarek, Radosław; Wolska, Nina; Świątkowska, Maria

doi:10.1016/j.bbrc.2020.03.143

Cited by 6 publications

(4 citation statements)

References 34 publications

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“…Furthermore, co-stimulation with ADP augments PDI surface expression (Crescente et al, 2016). Although the mechanism for PDI secretion in activated platelets remains a subject of (Sharda et al, 2015) because antagonism of the ADP receptor P2Y 12 reduces PDI secretion in thrombin-stimulated but not in resting platelets or unstimulated endothelial cells (Popielarski et al, 2020).…”

Section: Cells Referencementioning

confidence: 99%

“…Although the mechanism for PDI secretion in activated platelets remains a subject of debate, what is clear is that induced secretion of PDI from stimulated cells and constitutive secretion of PDI in steady‐state employ distinct mechanisms that involve different subcellular pools of PDI. For example, PDI secretion, as a consequence of thrombin‐activated platelets, requires ADP feedback signalling (Sharda et al, 2015) because antagonism of the ADP receptor P2Y 12 reduces PDI secretion in thrombin‐stimulated but not in resting platelets or unstimulated endothelial cells (Popielarski et al, 2020).…”

Section: Surface and Extracellular Location Of Pdimentioning

confidence: 99%

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Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Chiu

Chen

et al. 2021

British J Pharmacology

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Protein disulfide isomerase (PDI) is the prototypic member of the thiol isomerase family that catalyses disulfide bond rearrangement. Initially identified in the endoplasmic reticulum as folding catalysts, PDI and other members in its family have also been widely reported to reside on the cell surface and in the extracellular matrix. Although how PDI is exported and retained on the cell surface remains a subject of debate, this unique pool of PDI is developing into an important mechanism underlying the redox regulation of protein sulfhydryls that are critical for the cellular activities under various disease conditions. This review aims to provide an overview of the pathophysiological roles of surface and extracellular PDI and their underlying molecular mechanisms.Understanding the involvement of extracellular PDI in these diseases will advance our knowledge in the molecular aetiology to facilitate the development of novel pharmacological strategies by specifically targeting PDI in extracellular compartments.

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Section: Cells Referencementioning

confidence: 99%

Section: Surface and Extracellular Location Of Pdimentioning

confidence: 99%

Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Chiu

Chen

et al. 2021

British J Pharmacology

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“…To further complement this scenario, it is worth mentioning that the secretion of platelet PDI (protein disulphide isomerase)—a key enzyme involved in the regulation of TF prothrombotic activity 30 —is also controlled by P2Y 12 thus emphasizing an overall consistent and uniform regulation of the prothrombotic activity of platelets. 31 Clearly, the platelet-associated prothrombotic response may be elicited through multiple pathways including, for instance, activation of the thrombin receptors PAR-1 and PAR-4. 32 , 33 The possible regulation of platelet-associated TF expression by these other signaling pathways was not analyzed being out of the scope of the study.…”

Section: Discussionmentioning

confidence: 99%

Cell Surface Platelet Tissue Factor Expression: Regulation by P2Y ₁₂ and Link to Residual Platelet Reactivity

Brambilla,

Becchetti,

Rovati

et al. 2023

ATVB

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BACKGROUND: ADP-induced platelet activation leads to cell surface expression of several proteins, including TF (tissue factor). The role of ADP receptors in platelet TF modulation is still unknown. We aimed to assess the (1) involvement of P2Y 1 and P2Y 12 receptors in ADP-induced TF exposure; (2) modulation of TF pos -platelets in anti-P2Y 12 –treated patients with coronary artery disease. Based on the obtained results, we revisited the intracellular localization of TF in platelets. METHODS: The effects of P2Y 1 or P2Y 12 antagonists on ADP-induced TF expression and activity were analyzed in vitro by flow cytometry and thrombin generation assay in blood from healthy subjects, P2Y 12 −/− , and patients with gray platelet syndrome. Ex vivo, P2Y 12 inhibition of TF expression by clopidogrel/prasugrel/ticagrelor, assessed by VASP (vasodilator-stimulated phosphoprotein) platelet reactivity index, was investigated in coronary artery disease (n=238). Inhibition of open canalicular system externalization and electron microscopy (TEM) were used for TF localization. RESULTS: In blood from healthy subjects, stimulated in vitro by ADP, the percentage of TF pos -platelets (17.3±5.5%) was significantly reduced in a concentration-dependent manner by P2Y 12 inhibition only (−81.7±9.5% with 100 nM AR-C69931MX). In coronary artery disease, inhibition of P2Y 12 is paralleled by reduction of ADP-induced platelet TF expression (VASP platelet reactivity index: 17.9±11%, 20.9±11.3%, 40.3±13%; TF pos -platelets: 10.5±4.8%, 9.8±5.9%, 13.6±6.3%, in prasugrel/ticagrelor/clopidogrel-treated patients, respectively). Despite this, 15% of clopidogrel good responders had a level of TF pos -platelets similar to the poor-responder group. Indeed, a stronger P2Y 12 inhibition (130-fold) is required to inhibit TF than VASP. Thus, a VASP platelet reactivity index <20% (as in prasugrel/ticagrelor-treated patients) identifies patients with TF pos -platelets <20% (92% sensitivity). Finally, colchicine impaired in vitro ADP-induced TF expression but not α-granule release, suggesting that TF is open canalicular system stored as confirmed by TEM and platelet analysis of patients with gray platelet syndrome. CONCLUSIONS: Data show that TF expression is regulated by P2Y 12 and not P2Y 1 ; P2Y 12 antagonists downregulate the percentage of TF pos -platelets. In clopidogrel good-responder patients, assessment of TF pos -platelets highlights those with residual platelet reactivity. TF is stored in open canalicular system, and its membrane exposure upon activation is prevented by colchicine.

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“…During tissue damage, exposure to eADO changes the expression pattern of adhesion molecules, thus deregulating immune cells' attachment to the endothelium and their extravasation to the inflammation site [111]. It was recently shown that prolonged exposure to the non-selective AR agonist NECA may stimulate cancer cell movement through the endothelium and could thus contribute to metastasis; such effects were not seen following short exposure [112]. Although the ARs responsible for this outcome were not identified, these findings illustrate the spatial and temporal significance of AR targeting.…”

Section: Migration and Angiogenesismentioning

confidence: 99%

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

Kotulová

Hajdúch

Džubák

2021

IJMS

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A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies.

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P2Y12 receptor antagonists and AR receptor agonists regulates Protein Disulfide Isomerase secretion from platelets and endothelial cells

Cited by 6 publications

References 34 publications

Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Cell Surface Platelet Tissue Factor Expression: Regulation by P2Y ₁₂ and Link to Residual Platelet Reactivity

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

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P2Y12 receptor antagonists and AR receptor agonists regulates Protein Disulfide Isomerase secretion from platelets and endothelial cells

Cited by 6 publications

References 34 publications

Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

Cell Surface Platelet Tissue Factor Expression: Regulation by P2Y 12 and Link to Residual Platelet Reactivity

Current Adenosinergic Therapies: What Do Cancer Cells Stand to Gain and Lose?

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Cell Surface Platelet Tissue Factor Expression: Regulation by P2Y ₁₂ and Link to Residual Platelet Reactivity