title: Androgen-sensitive hypertension associated with soluble guanylate cyclase-α1 deficiency is mediated by 20-HETE.
abstract: Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the α1-subunit of the NO receptor soluble guanylate cyclase (sGCα1 (-/-) mice) display sex- and strain-specific hypertension: male but not female sGCα1 (-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype. Via linkage analysis, we identified a suggestive quantitative trait locus associated with elevated blood pressure in male sGCα1 (-/-)S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE). Renal expression of Cyp4a12a in mice was associated with genetic background, sex, and testosterone levels. In addition, 20-HETE levels were higher in renal preglomerular microvessels of male sGCα1 (-/-)S6 than of male sGCα1 (-/-)B6 mice. Furthermore, treating male sGCα1 (-/-)S6 mice with the 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) lowered blood pressure. Finally, 20-HEDE rescued the genetic background- and testosterone-dependent impairment of acetylcholine-induced relaxation in renal interlobar arteries associated with sGCα1 deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGCα1 deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Ana C
authors.initials: AC
authors.lastname: Dordea
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Sara
authors.initials: S
authors.lastname: Vandenwijngaert
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Victor
authors.initials: V
authors.lastname: Garcia
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Robert E T
authors.initials: RE
authors.lastname: Tainsh
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Nathan
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Allen
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Raher
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Laurel T
authors.initials: LT
authors.lastname: Tainsh
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Wolfgang S
authors.initials: WS
authors.lastname: Lieb
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Sarah
authors.initials: S
authors.lastname: Mikelman
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Techonology, Cambridge, Massachusetts;
authors.forename: Christine
authors.initials: C
authors.lastname: Stevens
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Robrecht
authors.initials: R
authors.lastname: Thoonen
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;
authors.forename: Allyson G
authors.initials: AG
authors.lastname: Hindle
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Sips
authors.affiliation: Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Techonology, Cambridge, Massachusetts;
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts; Cardiology Division, Department of Medicine, Massachusetts General, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts; Cardiology Division, Department of Medicine, Massachusetts General, Harvard Medical School, Boston, Massachusetts.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Bloch
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts; Cardiology Division, Department of Medicine, Massachusetts General, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Malhotra
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York;
authors.forename: Michal L
authors.initials: ML
authors.lastname: Schwartzman
authors.affiliation: Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts; ebuys@mgh.harvard.edu.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D000072470:Cytochrome P450 Family 4 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D040641:Quantitative Trait Loci; D012737:Sex Factors; D000071756:Soluble Guanylyl Cyclase / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000097:blood
chemical_list: D000728:Androgens; D006893:Hydroxyeicosatetraenoic Acids; D013739:Testosterone; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C493210:Cyp4a12a protein, mouse; D000072470:Cytochrome P450 Family 4; D000071756:Soluble Guanylyl Cyclase
keywords: 20-HETE; cytochrome P450; hypertension; nitric oxide; soluble guanylate cyclase; vascular function