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Aim  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 ( PPAR α).    Methods  The effects induced by aspirin or  PPAR α agonist ( WY14643 ) on  MRP4  modulation were evaluated  in vitro  in a human megakaryoblastic DAMI cell line, in megakaryocytes ( MKs ) and in platelets obtained from human haematopoietic progenitor cell ( HPC ) cultures, and  in vivo  platelets obtained from aspirin treated healthy volunteers ( HV ).    Results  In  DAMI  cells, aspirin and  WY14643  treatment induced a significant increase in  MRP4  and  PPAR α expression. In human  MK s grown in the presence of either aspirin or  WY14643 ,  MRP4  and  PPAR α‐ 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  MK s and to transfer it to platelets was also confirmed  in vivo . In fact, we found the highest  MRP4 mRNA  and protein expression in platelets obtained from  HV  after 15 days' aspirin treatment.    Conclusions  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.

Aspirin influences megakaryocytic gene expression leading to up‐regulation of multidrug resistance protein‐4 in human platelets