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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.
AuthorsAna 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
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 310 Issue 11 Pg. H1790-800 (06 01 2016) ISSN: 1522-1539 [Electronic] United States
PMID27199131 (Publication Type: Journal Article)
CopyrightCopyright © 2016 the American Physiological Society.
Chemical References
  • Androgens
  • Hydroxyeicosatetraenoic Acids
  • Testosterone
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cyp4a12a protein, mouse
  • Cytochrome P450 Family 4
  • Soluble Guanylyl Cyclase
Topics
  • Androgens (pharmacology)
  • Animals
  • Blood Pressure (drug effects, physiology)
  • Cytochrome P450 Family 4 (genetics)
  • Female
  • Genetic Linkage
  • Hydroxyeicosatetraenoic Acids (metabolism)
  • Hypertension (genetics, metabolism)
  • Kidney (drug effects, metabolism)
  • Male
  • Mice
  • Mice, Knockout
  • Quantitative Trait Loci
  • Sex Factors
  • Soluble Guanylyl Cyclase (genetics, metabolism)
  • Testosterone (blood)

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