Inhibition of Soluble Epoxide Hydrolase Increases Coronary Flow and Improves Cardiac Work in Mice

Abstract

We tested the hypothesis that compromising hydrolysis/degradation of epoxyeicosatrienoic acids (EETs) via deletion of the gene encoding soluble epoxide hydrolase (sEH) improves coronary circulatory response to myocardial work in mice. Hearts were isolated from male wild type (WT) and sEH knockout (KO) mice and perfused with constant flow at different pre‐loads. Compared to the WT controls, sEH‐KO hearts required significantly greater basal coronary flow to maintain the perfusion pressure at 100 mmHg suggesting a reduced basal coronary resistance. Increases in cardiac work initiated greater reduction of coronary flow resistance in sEH‐KO than in WT mice. Moreover, an improved cardiac contractile function was observed in response to increases in pre‐load in sEH‐KO mice. Adaptation of the coronary circulation in sEH‐KO hearts in response to increased work loads was prevented with the EET receptor antagonist 14,15‐EEZE, while inhibition of nitric oxide synthesis had no effect. Cardiac expression of CYP2J2 (EET synthase) was comparable in both groups of mice. Levels of EETs were dramatically higher in hearts from sEH‐KO which were accompanied with lower levels of DHETs (hydrolyzed EETs) compared to those of WT hearts. In conclusion, the elevation of cardiac EETs, as a function of deletion of sEH gene, plays significant roles in increasing coronary flow and improving cardiac function.