Functional consequences of soluble epoxide hydrolase inhibition in platelets: A comparative study of rat, mouse, and human platelets

Epoxyeicosatrienoic acids (EETs), nonclassical eicosanoids derived from arachidonic acid, act as signaling molecules that inhibit platelet aggregation. EETs are primarily metabolized by soluble epoxide hydrolase (sEH) into less active or inactive dihydroxyeicosatrienoic acids. Consequently, sEH has been considered a potential target for antiplatelet therapy, as its inhibition might enhance the anti-aggregatory activity of EETs, although this hypothesis has not been fully validated. This study aims to investigate whether sEH inhibition suppresses platelet aggregation. Treatment with 14,15-EET effectively inhibited the aggregation of platelets from rats and mice. However, the sEH inhibitor 12-(1-adamantylcarbamoylamino)dodecanoic acid (AUDA) alone had no direct effect. Instead, AUDA enhanced the anti-aggregatory effect of 14,15-EET in rat platelets but not in mouse platelets. Platelets from sEH-knockout ( Ephx2 ^−/−) mice showed no significant difference in aggregatory response compared to wild-type mice, and both mice exhibited similar thrombogenic potential in an arterial thrombosis model. Platelet sEH activity varied significantly among species, following the order: rat > human ≫ mouse. Notably, AUDA also enhanced the anti-aggregatory effect of 14,15-EET in human platelets, as observed in rat platelets. In conclusion, sEH inhibitors may lack sufficient antiplatelet activity as standalone agents but could serve as effective adjuncts to antiplatelet therapies. Additionally, given the inherently low sEH activity in mouse platelets compared to human platelets, mice may be an unsuitable model for studying sEH-related platelet function.