Aspirin influences megakaryocytic gene expression leading to up‐regulation of multidrug resistance protein‐4 in human platelets. (December 2014)

• Record Type: Journal Article
• Authors: Massimi, Isabella; Guerriero, Raffaella; Lotti, Lavinia Vittoria; Lulli, Valentina; Borgognone, Alessandra; Romani, Federico; Barillà, Francesco; Gaudio, Carlo; Gabbianelli, Marco; Frati, Luigi; Pulcinelli, Fabio M.
• Is Part Of: British journal of clinical pharmacology. Volume 78:Number 6(2014:Dec.)
• Page Start: 1343
• Page End: 1353
• Publication Date: 2014-12
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12432
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12432-sec-0001" sec-type="section"> <title>Aim</title> <p>The aim of the study was to investigate whether human megakaryocytic cells have an adaptive response to aspirin treatment, leading to an enhancement of multidrug resistance protein‐4 (MRP4) expression in circulating platelets responsible for a reduced aspirin action. We recently found that platelet MRP4 overexpression has a role in reducing aspirin action in patients after by‐pass surgery. Aspirin enhances MRP4‐mRNA levels in rat liver and drug administration transcriptionally regulates MRP4 gene expression through peroxisome proliferator‐activated receptor‐α (PPARα).</p> </sec> <sec id="bcp12432-sec-0002" sec-type="section"> <title>Methods</title> <p>The effects induced by aspirin or PPARα agonist (WY14643) on MRP4 modulation were evaluated <italic>in vitro</italic> in a human megakaryoblastic DAMI cell line, in megakaryocytes (MKs) and in platelets obtained from human haematopoietic progenitor cell (HPC) cultures, and <italic>in vivo</italic> platelets obtained from aspirin treated healthy volunteers (HV).</p> </sec> <sec id="bcp12432-sec-0003" sec-type="section"> <title>Results</title> <p>In DAMI cells, aspirin and WY14643 treatment induced a significant increase in MRP4 and PPARα expression. In human MKs grown in the presence of either aspirin or WY14643, MRP4 and PPARα‐mRNA were higher than in control cultures and derived platelets showed an enhancement in MRP4 protein expression. The ability of aspirin to modulate MRP4 expression in MKs and to transfer it to platelets was also confirmed <italic>in vivo</italic>. In fact, we found the highest MRP4 mRNA and protein expression in platelets obtained from HV after 15 days' aspirin treatment.</p> </sec> <sec id="bcp12432-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The present study provides evidence, for the first time, that aspirin treatment affects the platelet protein pattern through MK genomic modulation. This work represents an innovative and attractive approach, useful both to identify patients less sensitive to aspirin and to improve pharmacological treatment in cardiovascular high‐risk patients.</p> </sec> </abstract>