Aspirin effects on platelet gene expression are associated with a paradoxical, increase in platelet function.

Journal Article (Journal Article)

Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1 (COX-1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on- and off-target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified platelet mRNA sequencing to test the hypothesis that aspirin's effects on the platelet transcriptome are associated with platelet function. We prospectively recruited 74 adult volunteers for a randomized crossover study of 81- vs. 325 mg/day, each for 4 weeks. Using mRNA sequencing of purified platelets collected before and after each 4-week exposure, we identified 208 aspirin-responsive genes with no evidence for dosage effects. In independent cohorts of healthy volunteers and patients with diabetes, we validated aspirin's effects on five genes: EIF2S3, CHRNB1, EPAS1, SLC9A3R2 and HLA-DRA. Functional characterization of the effects of aspirin on mRNA as well as platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor of protein synthesis. Database searches for small molecules that mimicked the effects of aspirin on platelet gene expression in vitro identified aspirin but no other molecules that share aspirin's known mechanisms of action. The effects of aspirin on platelet mRNA were correlated with higher levels of platelet function both at baseline and after aspirin exposure-an effect that counteracts aspirin's known antiplatelet effect. In summary, this work collectively demonstrates a dose-independent effect of aspirin on the platelet transcriptome that counteracts the well-known antiplatelet effects of aspirin.

Full Text

Duke Authors

Cited Authors

  • Myers, RA; Ortel, TL; Waldrop, A; Dave, S; Ginsburg, GS; Voora, D

Published Date

  • May 2022

Published In

Volume / Issue

  • 88 / 5

Start / End Page

  • 2074 - 2083

PubMed ID

  • 34705291

Pubmed Central ID

  • PMC9007832

Electronic International Standard Serial Number (EISSN)

  • 1365-2125

Digital Object Identifier (DOI)

  • 10.1111/bcp.15127

Language

  • eng

Conference Location

  • England