Nonsteroidal anti-inflammatory drugs in-vitro and in-vivo treatment and Multidrug Resistance Protein 4 expression in human platelets

Temperilli, Flavia; Franco, Manuela Di; Massimi, Isabella; Guarino, Maria; Guzzo, Maria Paola; Valesini, Guido; Frati, Luigi; Pulcinelli, Fabio M.

doi:10.1016/j.vph.2015.06.016

Cited by 20 publications

(21 citation statements)

References 26 publications

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“…Moreover, platelets from patients with osteoarthritis, who are regular NSAID users, have an increased platelet reactivity due to an higher expression of MRP4. 25 Importantly, emerging studies support an association between high on-aspirin treatment residual platelet reactivity and adverse clinical outcomes in patients with cardiovascular and cerebrovascular disease. [26][27][28][29] A recent study has shown that targeted inhibition of miR-21 maturation with designed RNA-binding proteins is very important useful in the oncogenic treatment of tumors, 30 suggesting that this treatment can also be translated in other situations.…”

Section: Discussionmentioning

confidence: 99%

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Massimi

Alemanno

Guarino

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundA mechanism involved in high on‐aspirin treatment residual platelet reactivity is platelet multidrug resistance protein 4 (MRP4) overexpression. Aspirin enhances platelet MRP4 expression with a PPARα‐dependent mechanism and reduces miR‐21 expression that, in turn, downregulates PPARα expression.ObjectiveThe aim of our study was to verify the relationship between miR‐21 and MRP4‐PPARα levels induced by aspirin treatment.MethodsWe evaluated the changes in MRP4‐PPARα, mRNA, MRP4 protein, and miR‐21 expression induced by aspirin in: (i) in vitro–treated megakaryoblastic cell line (DAMI), (ii) primary megakaryocytes cultures and derived platelets, (iii) healthy volunteers’ platelets treated with aspirin, and (iv) aspirinated patients (aspirin‐treated patients) and in a control population (control).ResultsWe observed an aspirin‐induced reverse relationship between the expression of miR‐21 and PPARα‐MRP4. In DAMI cells the miR‐21 mimic transfection reduces PPARα and MRP4 expression, even if cells were treated with aspirin after transfection. MiR‐21 inhibitor transfection induces PPARα and MRP4 expression that are not enhanced by aspirin treatment. In human megakaryocytes, aspirin treatment lead to a miR‐21 downregulation and a MRP4 upregulation and this trend is confirmed in derived platelets. In aspirin‐treated volunteers, an inverse relationship between miR‐21 and MRP4 platelet expression was found after aspirin treatment. A similar negative relationship was found in aspirin‐treated patients vs the control population.ConclusionThe results reported in this study provide information that aspirin induces the modulation of platelet miR‐21 expression levels and this modulation can be responsible for MRP4 enhancement in circulating platelets.

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Section: Discussionmentioning

confidence: 99%

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Massimi

Alemanno

Guarino

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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“…Two-thirds of the PRP were drawn, without disturbing the buffy coat layer, in order to prevent contamination. PRP, transferred into a another new sterile tube, was mixed with ACD to avoid platelet activation, and centrifuged at 900 g for 10 min at 20°C (with no brake applied) [40].…”

Section: Platelets Separationmentioning

confidence: 99%

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Capozzi

Riitano

Recalchi

et al. 2020

Preprint

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Anti-phospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity associated with the presence of “anti-phospholipid antibodies”. Thrombosis may be the result of a hypercoagulable state related to activation of endothelial cells and platelets by anti-2-glycoprotein I (β2-GPI) antibodies. Anti-β2-GPI antibodies induce a proinflammatory and procoagulant phenotype in these cells that, after activation, express Tissue Factor (TF), the major initiator of the clotting cascade, playing a role in thrombotic manifestations. Moreover, TF expression may also be induced by Heparanase, an endo--D-glucuronidase, that generates heparan sulfate fragments, regulating inflammatory responses. In this study we analyzed, in human platelets and endothelial cells, the effect of a new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivative (RDS3337), able to inhibit Heparanase activity, on signal transduction pathway leading to TF expression triggered by anti-β2-GPI. Platelets and endothelial cells were incubated with affinity purified anti-β2-GPI after pretreatment with RDS3337. Cell lysates were analyzed for phospho-interleukin-1 receptor-associated kinase 1 (IRAK1), phospho-p65 nuclear factor kappa B (NF-κB) and TF by Western blot. IRAK phosphorylation and consequent NF-κB activation, as well as TF expression, triggered by anti-β2-GPI treatment were significantly prevented by previous pretreatment with RDS3337. In the same vein, pretreatment with RDS3337 prevented platelet aggregation and ATP release triggered by anti-β2-GPI antibodies. These findings support the view of Heparanase involvement in a prothrombotic state related to APS syndrome, suggesting a novel target to regulate overexpression of procoagulant protein(s).

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“…Finally, NSAIDs, including aspirin, increase ABCC4 expression 45 , 77 . ABCC4-mediated aspirin extrusion from the platelet cytosol causes an incomplete COX-1 inhibition in persons after coronary artery bypass graft surgery (45) .…”

Section: Discussionmentioning

confidence: 99%

Platelet Transcriptome Profiling in HIV and ATP-Binding Cassette Subfamily C Member 4 (ABCC4) as a Mediator of Platelet Activity

Marcantoni

Allen

Cambria

et al. 2018

JACC: Basic to Translational Science

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Nonsteroidal anti-inflammatory drugs in-vitro and in-vivo treatment and Multidrug Resistance Protein 4 expression in human platelets

Cited by 20 publications

References 26 publications

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Platelet Transcriptome Profiling in HIV and ATP-Binding Cassette Subfamily C Member 4 (ABCC4) as a Mediator of Platelet Activity

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