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

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.

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Correspondence to Emmanuel S Buys.

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Vandenwijngaert, S., Dordea, A.C., Garcia, V. et al. Androgen-sensitive hypertension associated with soluble guanylate cyclase alpha1 deficiency is mediated by 20-HETE. BMC Pharmacol Toxicol 16, A97 (2015). https://doi.org/10.1186/2050-6511-16-S1-A97

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Keywords

  • Nitric Oxide
  • Quantitative Trait Locus
  • Vascular Dysfunction
  • Soluble Guanylate Cyclase
  • Renal Expression