Volume 11 Supplement 1

5th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

Genetic mapping of a modifier locus affecting hypertension in soluble guanylate cyclase α1 deficient mice

  • Emmanuel S Buys1Email author,
  • Michael J Raher1,
  • Andrew Kirby2,
  • Sarah R Hayton1,
  • Laurel T Tainsh1,
  • Patrick Y Sips1,
  • Peter Brouckaert3,
  • Mark J Daly2 and
  • Kenneth D Bloch1
BMC Pharmacology201111(Suppl 1):P14

https://doi.org/10.1186/1471-2210-11-S1-P14

Published: 1 August 2011

Background

We previously reported that male mice deficient in the α1 subunit of the NO receptor soluble guanylate cyclase (sGCα1-/- mice), an important nitric oxide (NO) receptor, are hypertensive [1]. The phenotype depends on the genetic background: sGCα1-/- mice on a 129S6 (S6) background (sGCα1-/-S6) but not on a C57BL/6 (B6) background

(sGCα1-/-B6) develop hypertension [2]. These findings suggest that hypertension associated with sGCα1-deficiency is modulated by genetic factors. We aimed to identify modifier genes underlying the hypertension in sGCα1-/-S6 mice.

Materials and methods

Mean arterial blood pressure (MAP) was measured invasively in 280 male F2 offspring from a sGCα1-/-S6 X sGCα1-/-B6 intercross (sGCα1-/-F2). All mice were genotyped with a genome-wide panel of 150 SNP markers for linkage analysis using the Sequenom MassArray system and MAPMAKER/QTL. Renin-1c and renin-2d genotyping was performed using gene-specific primers. Plasma renin activity (PRA) and aldosterone were measured in anesthetized male S6 wild-type (WTS6) and sGCα1-/-S6 mice by radioimmunoassay and enzyme-linked immunoassay, respectively. The renin angiotensin system (RAS) was blocked by treating mice with either the aldosterone receptor antagonist, Spironolactone (100 mg/kg/day, subcutaneous pellet for 7 days), or the renin inhibitor, Aliskiren (200mg/kg/day, by gavage for 10 days).

Results

MAP in sGCα1-/-F2 mice varied between values observed in sGCα1-/-S6 and sGCα1-/-B6 mice. Linkage analysis identified a locus on chromosome 1 with a highly significant logarithm of odds (LOD) score of 6.1. This region is syntenic with previously identified hypertension-related QTLs in the human and rat genome and contains the gene coding for renin. Importantly, B6 mice have one renin gene (renin-1c), and S6 mice have two renin genes (renin-1d and renin-2). Presence of the renin-1d and renin-2 genes correlated significantly with elevated MAP in the F2 mice (P<0.0001). PRA was higher in sGCα1-/-S6 than in WTS6 mice (0.29±0.01 vs. 0.23±0.03 µg angiotensin 1/ml/hr, respectively, P<0.05). Similarly, plasma aldosterone levels were higher in sGCα1-/-S6 than in WTS6 mice (0.47±0.03 vs 0.34±0.03 ng/ml, respectively, P<0.05). Treatment with Spironolactone or Aliskiren normalized blood pressure in sGCα1-/-S6 (117±5 vs 146±2 mmHg, in Spironolactone and vehicle-treated mice, respectively, P<0.001, and 100±7 vs 148±4 mmHg, in Aliskiren and vehicle-treated mice, respectively, P<0.001).

Conclusion

Together, these data identify renin as a possible genetic modifier of blood pressure in a setting of deficient NO-cGMP signaling. Furthermore, these findings highlight the importance of sGC in the regulation of the renin-angiotensin system (RAS) and suggest that sGC may be a therapeutic target in RAS-dependent hypertension.

Authors’ Affiliations

(1)
Department of Anesthesia Critical Care and Pain Medicine, Massachusetts General Hospital
(2)
Department of Medicine, Center for Human Genetic Research, Massachusetts General Hospital
(3)
VIB Department of Molecular Biomedical Research, Ghent University

References

  1. Buys ES, Sips P, Vermeersch P, Raher MJ, Rogge E, Ichinose F, Dewerchin M, Bloch KD, Janssens S, Brouckaert P: Gender-specific hypertension and responsiveness to nitric oxide in sGCα1 knockout mice. Cardiovasc Res. 2008, 79: 179-186. 10.1093/cvr/cvn068.View ArticlePubMedGoogle Scholar
  2. Buys ES, Cauwels A, Raher MJ, Passeri JJ, Hobai M, Cawley SM, Rauwerdink KM, Thibault H, Sips PY, Thoonen R, Scherrer-Crosbie M, Ichinose F, Brouckaert P, Bloch KD: sGCα1β1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models. Am J Physiol. 2009, 297: H654-663. 10.1152/ajpcell.00059.2009.View ArticleGoogle Scholar

Copyright

© Buys et al; licensee BioMed Central Ltd. 2011

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/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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