Atherothrombotic cardiovascular (CV) disease leads to platelet aggregation and thrombus
formation. Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA), and was
shown to reduce ischemic events in high-risk patients (REDUCE-IT). IPE is approved
by Health Canada to reduce CV risk among patients with elevated TG levels as an add-on
to maximally tolerated statin therapy. In this study, the effects of EPA on expression
of proteins associated with platelet activation and aggregation were measured in cytokine
(IL-6) treated pulmonary and vascular endothelial cells (ECs).
METHODS AND RESULTS
Human pulmonary ECs (PECs) and umbilical vein ECs (HUVECs) were treated with vehicle
or EPA (40/10 µM in PECs/HUVECs) and IL-6 (12 ng/mL) for 24 h. Proteomic analysis
was performed using liquid chromatography/mass spectroscopy that detected modulation
of >1,000 proteins. Proteins which showed significantly (p < 0.05) greater than 1-fold
change between treatment groups were further assessed. EPA significantly downregulated
a total of 36 proteins involved in platelet activation, signaling, aggregation, in
EC following cytokine exposure. Platelet endothelial cell adhesion molecule (PECAM)
was downregulated in both HUVECs and PECs (1.2-fold) by EPA. In PECs, EPA significantly
modulated 26 additional proteins related to platelet activation, including amyloid-beta
precursor protein (1.1-fold decrease) and thrombin receptor (PAR-1,1.3-fold decrease).
In HUVECs, the expression of nine other proteins were modulated related to platelet
activation, including superoxide dismutase (1.6-fold increase).
EPA significantly reduced expression of multiple EC proteins required for platelet
activation and aggregation, including PECAM in both pulmonary and vascular tissues.
These findings indicate potential novel anti-platelet mechanisms for EPA that may
account for reduced ischemic events in REDUCE-IT.