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

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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 alpha(1)-subunit of the NO receptor soluble guanylate cyclase (sGC(alpha 1)(-/-) mice) display sex-and strain-specific hypertension: male but not female sGC(alpha 1)(-/-) 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 sGC(alpha 1)(-/-) S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy5,8,11,14- 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 sGC(alpha 1)(-/-) S6 than of male sGC(alpha 1)(-/-) B6 mice. Furthermore, treating male sGC(alpha 1)(-/-) 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 sGC(alpha 1)(-/-) deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGC(alpha 1)(-/-) deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.
Keywords
vascular function, hypertension, cytochrome P450, GENOME-WIDE ASSOCIATION, BLOOD-PRESSURE, 20-HYDROXYEICOSATETRAENOIC ACID, ENDOTHELIAL DYSFUNCTION, GENDER-DIFFERENCES, COMMON VARIANTS, KNOCKOUT MICE, CYP4A11 GENE, SYNTHASE, POLYMORPHISMS, soluble guanylate cyclase, nitric oxide, 20-HETE

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Chicago
Dordea, Ana C, Sara Vandenwijngaert, Victor Garcia, Robert ET Tainsh, Daniel I Nathan, Kaitlin Allen, Michael J Raher, et al. 2016. “Androgen-sensitive Hypertension Associated with Soluble Guanylate Cyclase-α₁ Deficiency Is Mediated by 20-HETE.” American Journal of Physiology-heart and Circulatory Physiology 310 (11): H1790–H1800.
APA
Dordea, A. C., Vandenwijngaert, S., Garcia, V., Tainsh, R. E., Nathan, D. I., Allen, K., Raher, M. J., et al. (2016). Androgen-sensitive hypertension associated with soluble guanylate cyclase-α₁ deficiency is mediated by 20-HETE. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 310(11), H1790–H1800.
Vancouver
1.
Dordea AC, Vandenwijngaert S, Garcia V, Tainsh RE, Nathan DI, Allen K, et al. Androgen-sensitive hypertension associated with soluble guanylate cyclase-α₁ deficiency is mediated by 20-HETE. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY. 2016;310(11):H1790–H1800.
MLA
Dordea, Ana C, Sara Vandenwijngaert, Victor Garcia, et al. “Androgen-sensitive Hypertension Associated with Soluble Guanylate Cyclase-α₁ Deficiency Is Mediated by 20-HETE.” AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 310.11 (2016): H1790–H1800. Print.
@article{8023210,
  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 alpha(1)-subunit of the NO receptor soluble guanylate cyclase (sGC(alpha 1)(-/-) mice) display sex-and strain-specific hypertension: male but not female sGC(alpha 1)(-/-) 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 sGC(alpha 1)(-/-) S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy5,8,11,14- 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 sGC(alpha 1)(-/-) S6 than of male sGC(alpha 1)(-/-) B6 mice. Furthermore, treating male sGC(alpha 1)(-/-) 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 sGC(alpha 1)(-/-) deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGC(alpha 1)(-/-) deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.},
  author       = {Dordea, Ana C and Vandenwijngaert, Sara and Garcia, Victor and Tainsh, Robert ET and Nathan, Daniel I and Allen, Kaitlin and Raher, Michael J and Tainsh, Laurel T and Zhang, Fan and Lieb, Wolfgang S and Mikelman, Sarah and Kirby, Andrew and Stevens, Christine and Thoonen, Robrecht and Hindle, Allyson G and Sips, Patrick and Falck, John R and Daly, Mark J and Brouckaert, Peter and Bloch, Kenneth D and Bloch, Donald B and Malhotra, Rajeev and Schwartzman, Michal L and Buys, Emmanuel S},
  issn         = {0363-6135},
  journal      = {AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY},
  keyword      = {vascular function,hypertension,cytochrome P450,GENOME-WIDE ASSOCIATION,BLOOD-PRESSURE,20-HYDROXYEICOSATETRAENOIC ACID,ENDOTHELIAL DYSFUNCTION,GENDER-DIFFERENCES,COMMON VARIANTS,KNOCKOUT MICE,CYP4A11 GENE,SYNTHASE,POLYMORPHISMS,soluble guanylate cyclase,nitric oxide,20-HETE},
  language     = {eng},
  number       = {11},
  pages        = {H1790--H1800},
  title        = {Androgen-sensitive hypertension associated with soluble guanylate cyclase-\ensuremath{\alpha}\unmatched{2081} deficiency is mediated by 20-HETE},
  url          = {http://dx.doi.org/10.1152/ajpheart.00877.2015},
  volume       = {310},
  year         = {2016},
}

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