Androgen-sensitive hypertension associated with soluble guanylate cyclase-α1 deficiency is mediated by 20-HETE

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, J R Falck, Mark J. Daly, Peter Brouckaert, Kenneth D. BlochDonald B. Bloch, Rajeev Malhotra, Michal L. Schwartzman, Emmanuel S. Buys

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 sGCα1deficiency. 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.

Original languageEnglish (US)
Pages (from-to)H1790-H1800
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume310
Issue number11
DOIs
StatePublished - Jun 2016

Keywords

  • 20-HETE
  • Cytochrome P450
  • Hypertension
  • Nitric oxide
  • Soluble guanylate cyclase
  • Vascular function

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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