Genetic Variation in Soluble Epoxide Hydrolase ( EPHX2 ) Is Associated With Forearm Vasodilator Responses in Humans

Abstract

Abstract-Cytochrome P450-derived epoxyeicosatrienoic acids are potent vasodilators in preclinical models and are hydrolyzed by soluble epoxide hydrolase (EPHX2). Associations between the EPHX2 Lys55Arg and Arg287Gln polymorphisms and cardiovascular disease risk have been reported; however, their impact on vascular function in humans has not been investigated. In 265 volunteers (198 white, 67 black American), forearm blood flow was measured by strain-gauge venous occlusion plethysmography at baseline and in response to bradykinin, methacholine, and sodium nitroprusside. Forearm vascular resistance was calculated as mean arterial pressure/forearm blood flow. In white Americans, Lys55Arg genotype was associated with vasodilator response to bradykinin, such that forearm blood flow was significantly lower (Pϭ0.043) and forearm vascular resistance was significantly higher (Pϭ0.013) in Arg55 variant allele carriers compared to wild-type individuals. Significant associations were also observed with methacholine and sodium nitroprusside. In contrast, no relationship was observed in black Americans. In black Americans, Arg287Gln genotype was associated with vasodilator response to bradykinin. Although the difference in forearm blood flow did not reach statistical significance (Pϭ0.058), forearm vascular resistance was significantly lower (Pϭ0.037) in Gln287 variant allele carriers compared to wild-type individuals. Significant associations were also observed with methacholine and sodium nitroprusside. In white Americans, Gln287 variant allele carriers did not exhibit significantly higher forearm blood flow (Pϭ0.128) or lower forearm vascular resistance (Pϭ0.080). Genetic variation in EPHX2 is associated with forearm vasodilator responses in a bradykinin receptorand endothelium-independent manner, suggesting an important role for soluble epoxide hydrolase in the regulation of vascular function in humans. Key Words: Soluble epoxide hydrolase Ⅲ EPHX2 polymorphism Ⅲ bradykinin Ⅲ endothelium-derived factors C ytochrome P450 (CYP) epoxygenase enzymes from the CYP2J and CYP2C subfamilies catalyze the oxidative metabolism of arachidonic acid to epoxyeicosatrienoic acids (EETs). 1 EETs are synthesized in the endothelium and cause vasodilation in numerous vascular beds via activation of calcium-sensitive potassium channels (BK Ca ) and smooth muscle cell hyperpolarization. 2,3 Consequently, CYP-derived EETs are regarded as one of the primary endothelium-derived hyperpolarizing factors. 2 Soluble epoxide hydrolase (sEH) rapidly hydrolyzes EETs to less biologically active dihydroxyeicosatrienoic acid metabolites. 4 Pharmacological inhibition of sEH increases cellular and circulating EET levels, potentiates EET-mediated vasodilation, and lowers blood pressure in preclinical models. 4 -6 Importantly, sEH inhibitors are currently in clinical development for the treatment of hypertension.Associations between polymorphisms in the gene encoding sEH (EPHX2) and cardiovascular and cerebrovascular disease risk in humans have been reported re...

Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation

“…Several human genetic studies have associated the polymorphs of sEH with a range of diseases (11)(12)(13)(14). Previous work demonstrated there are signifi cant differences in the specifi c activity of the SNPs using surrogate substrates ( 10,15,17 ).…”

“…Lower plasma FA epoxide-to-diol ratios were observed in K55R Caucasians but not African Americans ( 38 ), suggesting that other factors besides sEH catalytic activity play a role in the pathologies associated with this SNP. There is no indication in the literature that the pathologies associated with the other SNPs resulted from altered EpFA metabolism (11)(12)(13)(14). Separately, the observation that in some tissues the concentration of sEH ( Table 3 ) is higher than its natural substrates ( 1,18,19 ) suggests that >90% inhibition of the enzyme is needed to signifi cantly alter EpFA metabolism is some tissues, such as the liver and kidneys.…”

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

“…Decreased vascular resistance, suggesting a potential protective effect towards the development of hypertension, was found in Black American carriers of the EPHX2 287Gln variant with respect to "wild type" subjects [99].…”

“…Finally, the functionality of these SNPs was tested on endothelial dependent and independent vasodilatatory capacity, using intra-arterial infusion of vasoactive compounds and strain-gauge venous occlusion plethysmography. A decrease in forearm blood flow, index of impaired endothelial function, was detected in white Americans for the 55Arg variant in response to the intra-arterial infusion of bradykinin, methacholine and sodium nitroprussiate [99].…”

Upregulation of soluble epoxide hydrolase in proximal tubular cells mediated proteinuria-induced renal damage

“…The activity of sEH is therefore thought to be a major determinant of EET bioavailability (6,14). Genetic deletion of sEH, as well as pharmacological inhibition, increases plasma EET levels and potentiates their effects (22,23); thus sEH inhibition has antihypertensive and anti-inflammatory effects. Indeed, sEH inhibition may reduce hypertension, myocardial infarct size, cerebral infarction, vascular remodeling and atherosclerosis, and even tobacco smoke-induced airway inflammation (5,13,30).…”