Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
Soluble epoxide hydrolase (sEH) is an enzyme responsible for metabolizing lipid epoxides into diols, with epoxyeicosatrienoic acids (EETs) among its most well-characterized substrates. Given the antiplatelet activity of EETs, it was hypothesized that inhibiting sEH would decrease platelet reactivity by building up EETs in platelets. Treatment with 14,15-EETs successfully inhibited the aggregatory response of rat and mouse platelets to collagen. However, contrary to expectations, the sEH inhibitor AUDA did not affect aggregation, and there was no discernible difference in reactivity between platelets from sEH-null (Ephx2-/-) and wild-type (WT) mice. Furthermore, in an arterial thrombosis model, the thrombogenic potential in Ephx2-/- mice was comparable to that in WT controls. Notably, sEH activity in mouse platelets was relatively low, comprising only 26 or 39% of that in rat or human platelets, respectively, and the ratio of sEH activity in platelets to liver was substantially lower in mice (0.011) compared to rats (0.845) or humans (0.045), indicating significant species differences. Although concurrent treatment with 14,15-EETs and AUDA reduced the response of rat platelets to collagen, such inhibition was not observed in AUDA-treated platelets from Ephx2-/- mice. In conclusion, sEH inhibition may not suffice to reduce aggregation but could desensitize platelets to aggregatory stimuli. However, this effect is not evident in mouse platelets, likely due to the inherently low activity of sEH. Therefore, the mouse model may not be suitable for studying platelet function in the context of sEH.
