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BMC Pharmacology and Toxicology

Open Access

Androgen-sensitive hypertension associated with soluble guanylate cyclase alpha1 deficiency is mediated by 20-HETE

  • Sara Vandenwijngaert1,
  • Ana C Dordea1,
  • Victor Garcia2,
  • Robert E Tainsh1,
  • Daniel I Nathan1,
  • Michael J Raher1,
  • Kaitlin Allen1,
  • Fan Zhang2,
  • Wolfgang S Lieb1,
  • Sarah Mikelman1,
  • Andrew Kirby3,
  • Christine Stevens3,
  • Robrecht Thoonen1,
  • Allyson Hindle1,
  • Patrick Y Sips4,
  • Rajeev Malhotra1,
  • Mark J Daly3,
  • Peter Brouckaert5,
  • Kenneth D Bloch1,
  • Michal Schwartzman2 and
  • Emmanuel S Buys1Email author
BMC Pharmacology and Toxicology201516(Suppl 1):A97

https://doi.org/10.1186/2050-6511-16-S1-A97

Published: 2 September 2015

Background

Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension. Previously, we reported gender- and strain-specific hypertension in mice deficient in the α1-subunit of the NO receptor soluble guanylate cyclase (sGCα1-/-): male mice on an Sv129/J (S6) but not a C57BL6/J (B6) background are hypertensive.

Methods and results

Via linkage analysis, we identified a quantitative trait locus (QTL) associated with elevated blood pressure in male sGCα1-/-S6 mice. This QTL encompasses CYP4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Renal expression of CYP4a12awas strain-, gender-, and testosterone-dependent:CYP4a12a gene expression was higher in male WT and sGCα1-/-S6 mice than in female S6 mice, or than in male and female, WT and sGCα1-/- B6 mice, higher in testosterone-treated S6 mice than in vehicle-treated S6 mice, and higher in sham-operated S6 mice than orchiectomized S6 mice. Also, 20-HETE levels were higher in renal preglomerular microvessels of male sGCα1-/- S6 than of sGCα1-/- B6 mice. Furthermore, the 20-HETE antagonist 20-6,15-HEDGE lowered blood pressure in male sGCα1-/- S6 but not WT mice. Finally, the more significant impairment of acetylcholine-induced relaxation of renal interlobar arteries in male sGCα1-/- S6 than sGCα1-/- B6 mice, in male sGCα1-/- S6 than WT S6 mice, and in male sham-operated sGCα1-/- S6 mice than orchiectomized sGCα1-/- S6 mice was rescued by 20-6,15-HEDGE.

Conclusion

Gender- and strain-specific hypertension and vascular dysfunction in sGCα1-/- S6 mice is associated with elevated CYP4a12a expression and 20-HETE levels, and is abrogated by antagonizing 20-HETE. These results corroborate our hypothesis that testosterone-induced CYP4a12a expression and a concomitant increase in 20-HETE production contribute to the hypertension associated with impaired NO-cGMP signaling and that CYP4a12a represents a candidate blood pressure modifying gene in the context of deficient NO-sGC signaling.

Authors’ Affiliations

(1)
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School
(2)
Department of Pharmacology, New York Medical College
(3)
Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School
(4)
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital
(5)
Department for Biomedical Molecular Biology, Ghent University

Copyright

© Vandenwijngaert et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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