Linking an insect enzyme to hypertension: angiotensin II–epoxide hydrolase interactions

Derived from arachidonic acid, epoxyeicosatrienoic acids function as antihypertensive and antihypertrophic mediators in the cardiovascular system. Epoxyeicosatrienoic acids are generated by soluble epoxide hydrolase, an enzyme hydrolyzing the epoxide moiety of juvenile hormones in insects, and are endothelium-derived hyperpolarizing factors that induce vessel dilation for cardioprotection. Pharmacological inhibition and genetic ablation of soluble epoxide hydrolase increases the level of epoxyeicosatrienoic acids. Recent findings suggest that the level of soluble epoxide hydrolase in the heart and endothelium is upregulated by angiotensin II in vitro in cultured cardiomyocytes and vascular endothelial cells and in vivo in rodent models. Treatment with soluble epoxide hydrolase-selective inhibitors in angiotensin II–infused hypertensive rats increases the level of epoxyeicosatrienoic acids, with attendant decrease in systolic blood pressure. Shear stress, the physiological stimulation of vessel dilation, downregulates soluble epoxide hydrolase and hence increases epoxyeicosatrienoic acid level in endothelial cells. Because of the close association of the angiotensin II/soluble epoxide hydrolase/epoxyeicosatrienoic acid system and blood pressure regulation, pharmacological inhibition of soluble epoxide hydrolase would be a useful approach to prevent and treat angiotensin II–induced cardiac hypertrophy and hypertension, as well as vascular impairments.