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. Bloch & 4 others Donald B. Bloch, Rajeev Malhotra, Michal L. Schwartzman, Emmanuel S. Buys

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 1 2016

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Androgens
Hypertension
S 6
Blood Pressure
Testosterone
Nitric Oxide
Kidney
Soluble Guanylyl Cyclase
20-hydroxy-5,8,11,14-eicosatetraenoic acid
guanylate cyclase 1
Quantitative Trait Loci
Vasoconstrictor Agents
Renal Artery
Microvessels
Acetylcholine
Blood Vessels
Molecular Biology
Cardiovascular Diseases
Phenotype
Genes

Keywords

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

ASJC Scopus subject areas

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

Cite this

Androgen-sensitive hypertension associated with soluble guanylate cyclase-α1 deficiency is mediated by 20-HETE. / Dordea, Ana C.; Vandenwijngaert, Sara; Garcia, Victor; Tainsh, Robert E T; Nathan, Daniel I.; Allen, Kaitlin; Raher, Michael J.; Tainsh, Laurel T.; Zhang, Fan; Lieb, Wolfgang S.; Mikelman, Sarah; Kirby, Andrew; Stevens, Christine; Thoonen, Robrecht; Hindle, Allyson G.; Sips, Patrick Y.; Falck, J R; Daly, Mark J.; Brouckaert, Peter; Bloch, Kenneth D.; Bloch, Donald B.; Malhotra, Rajeev; Schwartzman, Michal L.; Buys, Emmanuel S.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 310, No. 11, 01.06.2016, p. H1790-H1800.

Research output: Contribution to journalArticle

Dordea, AC, Vandenwijngaert, S, Garcia, V, Tainsh, RET, Nathan, DI, Allen, K, Raher, MJ, Tainsh, LT, Zhang, F, Lieb, WS, Mikelman, S, Kirby, A, Stevens, C, Thoonen, R, Hindle, AG, Sips, PY, Falck, JR, Daly, MJ, Brouckaert, P, Bloch, KD, Bloch, DB, Malhotra, R, Schwartzman, ML & Buys, ES 2016, 'Androgen-sensitive hypertension associated with soluble guanylate cyclase-α1 deficiency is mediated by 20-HETE', American Journal of Physiology - Heart and Circulatory Physiology, vol. 310, no. 11, pp. H1790-H1800. https://doi.org/10.1152/ajpheart.00877.2015
Dordea, Ana C. ; Vandenwijngaert, Sara ; Garcia, Victor ; Tainsh, Robert E T ; Nathan, Daniel I. ; Allen, Kaitlin ; Raher, Michael J. ; Tainsh, Laurel T. ; Zhang, Fan ; Lieb, Wolfgang S. ; Mikelman, Sarah ; Kirby, Andrew ; Stevens, Christine ; Thoonen, Robrecht ; Hindle, Allyson G. ; Sips, Patrick Y. ; Falck, J R ; Daly, Mark J. ; Brouckaert, Peter ; Bloch, Kenneth D. ; Bloch, Donald B. ; Malhotra, Rajeev ; Schwartzman, Michal L. ; Buys, Emmanuel S. / Androgen-sensitive hypertension associated with soluble guanylate cyclase-α1 deficiency is mediated by 20-HETE. In: American Journal of Physiology - Heart and Circulatory Physiology. 2016 ; Vol. 310, No. 11. pp. H1790-H1800.
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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.",
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AU - Dordea, Ana C.

AU - Vandenwijngaert, Sara

AU - Garcia, Victor

AU - Tainsh, Robert E T

AU - Nathan, Daniel I.

AU - Allen, Kaitlin

AU - Raher, Michael J.

AU - Tainsh, Laurel T.

AU - Zhang, Fan

AU - Lieb, Wolfgang S.

AU - Mikelman, Sarah

AU - Kirby, Andrew

AU - Stevens, Christine

AU - Thoonen, Robrecht

AU - Hindle, Allyson G.

AU - Sips, Patrick Y.

AU - Falck, J R

AU - Daly, Mark J.

AU - Brouckaert, Peter

AU - Bloch, Kenneth D.

AU - Bloch, Donald B.

AU - Malhotra, Rajeev

AU - Schwartzman, Michal L.

AU - Buys, Emmanuel S.

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N2 - 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.

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KW - Nitric oxide

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