title: Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans.
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 (P = 0.043) and forearm vascular resistance was significantly higher (P = 0.013) 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 (P = 0.058), forearm vascular resistance was significantly lower (P = 0.037) 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 (P = 0.128) or lower forearm vascular resistance (P = 0.080). Genetic variation in EPHX2 is associated with forearm vasodilator responses in a bradykinin receptor- and endothelium-independent manner, suggesting an important role for soluble epoxide hydrolase in the regulation of vascular function in humans.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599-7569, USA. craig_lee@unc.edu
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
authors.forename: Mias
authors.initials: M
authors.lastname: Pretorius
authors.forename: Robert N
authors.initials: RN
authors.lastname: Schuck
authors.forename: Lauranell H
authors.initials: LH
authors.lastname: Burch
authors.forename: Jackie
authors.initials: J
authors.lastname: Bartlett
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
mesh_terms: D000328:Adult; D044383:Black People; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology; D015331:Cohort Studies; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D005542:Forearm / Q000098:blood supply*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D012907:Smoking / Q000453:epidemiology / Q000235:genetics; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000235:genetics*; D014665:Vasodilator Agents / Q000494:pharmacology*; D044465:White People; D055815:Young Adult; D001741:Black or African American
chemical_list: D014665:Vasodilator Agents; D016210:Methacholine Chloride; D009599:Nitroprusside; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human; D001920:Bradykinin