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.
American journal of physiology. Heart and circulatory physiology. 2016 May 03 [Epub]
Ana C Dordea, Sara Vandenwijngaert, Victor Garcia, Robert E T Tainsh, Daniel I Nathan, Kaitlin Allen, Michael J Raher, Laurel T Tainsh, Fan Zhang, Wolfgang S Lieb, Sarah Mikelman, Andrew Kirby, Christine Stevens, Robrecht Thoonen, Allyson G Hindle, Patrick Y Sips, John R Falck, Mark J Daly, Peter Brouckaert, Kenneth D Bloch, Donald B Bloch, Rajeev Malhotra, Michal L Schwartzman, Emmanuel S Buys
Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Department of Pharmacology, New York Medical College, Valhalla, New York;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Department of Pharmacology, New York Medical College, Valhalla, New York;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, 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;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts;, Division of Cardiovascular Medicine, Department of Medicine Brigham and Women's Hospital, Boston, Massachusetts;, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas;, 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;, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; and., 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., 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., 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., Department of Pharmacology, New York Medical College, Valhalla, New York;, Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts; .