title: Arachidonic acid monooxygenase: Genetic and biochemical approaches to physiological/pathophysiological relevance.
abstract: Studies with rat genetic models of hypertension pointed to roles for the CYP2C and CYP4A arachidonic acid epoxygenases and ω-hydroxylases in tubular transport, hemodynamics, and blood pressure control. Further progress in defining their physiological functions and significance to human hypertension requires conclusive identifications of the relevant genes and proteins. Here we discuss unequivocal evidence of roles for the murine Cyp4a14, Cyp4a10, and Cyp2c44 genes in the pathophysiology of hypertension by showing that: (a) Cyp4a14(-/-) mice develop sexually dimorphic hypertension associated with renal vasoconstriction, and up-regulated expression of Cyp4a12a and pro-hypertensive 20-hydroxyeicosatetraenoic acid (20-HETE) levels, and b) Cyp4a10(-/-) and Cyp2c44(-/-) mice develop salt sensitive hypertension linked to downregulation or lack of the Cyp2c44 epoxygenase, reductions in anti-hypertensive epoxyeicosatrienoic acids (EETs), and increases in distal sodium reabsorption. Based on these studies, the human CYP4A11 and CYPs 2C8 and 2C9 genes and their products are identified as potential candidates for studies of the molecular basis of human hypertension.
authors.affiliation: Department of Medicine, Vanderbilt University Medical School, Nashville, TN 37232, USA. Electronic address: jorge.capdevila@vanderbilt.edu.
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Capdevila
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center , Dallas, TX 75390, USA. Electronic address: j.falck@utsouthwestern.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
mesh_terms: D000818:Animals; D001794:Blood Pressure; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012964:Sodium / Q000378:metabolism
chemical_list: D053503:Epithelial Sodium Channels; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D000090762:Cytochrome P-450 CYP2J2
keywords: 20-HETE; Arachidonic acid; EET; Epoxygenase; Hypertension; P450