Abstract
Chronic treatment with aspirin in healthy volunteers (HVs) is associated with recovery
of adenosine diphosphate (ADP)-induced platelet activation. The purinergic P2Y1 receptor exerts its effects via a Gq-protein, which is the same biochemical pathway activated by thromboxane-A2 receptor.
We hypothesized that recovery of ADP-induced platelet activation could be attributed
to increased P2Y1 expression induced by chronic aspirin exposure. We performed a multi-phase investigation
which embraced both in vitro and in vivo experiments conducted in (1) human megakaryoblastic
DAMI cells, (2) human megakaryocytic progenitor cell cultures, (3) platelets obtained
from HVs treated with aspirin and (4) platelets obtained from aspirin-treated patients.
DAMI cells treated with aspirin or WY14643 (PPARα agonist) had a significant up-regulation
of P2Y1 mRNA, which was shown to be a PPARα-dependent process. In human megakaryocytic progenitors,
in the presence of aspirin or WY14643, P2Y1 mRNA expression was higher than in mock culture. P2Y1 expression increased in platelets obtained from HVs treated with aspirin for 8 weeks.
Platelets obtained from patients who were on aspirin for more than 2 months had increased
P2Y1 expression and ADP-induced aggregation compared with patients on aspirin treatment
for less than a month. Overall, our results suggest that aspirin induces genomic changes
in megakaryocytes leading to P2Y1 up-regulation and that PPARα is the nuclear receptor involved in this regulation.
Since P2Y1 is coupled to the same Gq-protein of thromboxane-A2 receptor, platelet adaptation in response to pharmacological
inhibition seems not to be receptor specific, but may involve other receptors with
the same biochemical pathway.
Keywords
aspirin - purinergic receptors - PPARα - platelet reactivity
