MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation. Issue 3 (17th May 2018)

• Record Type: Journal Article
• Authors: Massimi, Isabella; Alemanno, Laura; Guarino, Maria L.; Guerriero, Raffaella; Frati, Luigi; Biasucci, Luigi; Pulcinelli, Fabio M.
• Is Part Of: Research and practice in thrombosis and haemostasis. Volume 2:Issue 3(2018)
• Page Start: 596
• Page End: 606
• Publication Date: 2018-05-17
• Subjects: aspirin -- biomarkers -- microrna -- platelets -- thrombosis; Thrombosis -- Periodicals; Hemostasis -- Periodicals; 616.135005
• DOI: 10.1002/rth2.12104
• Languages: English
• ISSNs: 2475-0379

Abstract

Abstract: Background: A 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. Objective: The aim of our study was to verify the relationship between miR‐21 and MRP4‐PPARα levels induced by aspirin treatment. Methods: We 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). Results: We 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. Conclusion: The 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.