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

Isabella Massimi1, Laura Alemanno1, Maria L Guarino1

  • 1Department of Experimental Medicine Sapienza-University of Rome Rome Italy.

Research and Practice in Thrombosis and Haemostasis
|July 27, 2018
PubMed
Abstract

Insights

Aspirin treatment reduces miR-21 levels, leading to increased platelet multidrug resistance protein 4 (MRP4) and PPARα expression. This explains residual platelet reactivity in patients on aspirin therapy.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Hematology

Background:

  • High on-aspirin treatment residual platelet reactivity is linked to platelet multidrug resistance protein 4 (MRP4) overexpression.
  • Aspirin enhances platelet MRP4 via a PPARα-dependent pathway, concurrently reducing miR-21, which downregulates PPARα.

Purpose of the Study:

  • To investigate the relationship between miR-21 and MRP4-PPARα levels following aspirin treatment.
  • To elucidate the role of miR-21 in aspirin-induced changes in platelet reactivity.

Main Methods:

  • Assessed changes in MRP4-PPARα, mRNA, protein, and miR-21 expression in vitro (DAMI cells) and in vivo (human megakaryocytes, platelets from healthy volunteers, and aspirin-treated patients).
  • Utilized miR-21 mimic and inhibitor transfections in cell lines to confirm regulatory pathways.

Main Results:

  • An inverse relationship between miR-21 and PPARα-MRP4 expression was observed post-aspirin treatment.
  • miR-21 mimic transfection reduced PPARα and MRP4, while inhibitor transfection increased them, independent of aspirin.
  • Aspirin induced miR-21 downregulation and MRP4 upregulation in human megakaryocytes and platelets, consistent with findings in patients.

Conclusions:

  • Aspirin modulates platelet miR-21 expression levels.
  • This modulation is a key factor responsible for the enhancement of MRP4 in circulating platelets, contributing to residual platelet reactivity.
Keywords:
aspirinbiomarkersmicrornaplateletsthrombosis

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