Volume 14 Supplement 1

6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

Genetic modifiers of hypertension in sGC-deficient mice

BMC Pharmacology and Toxicology201314(Suppl 1):O8

https://doi.org/10.1186/2050-6511-14-S1-O8

Published: 29 August 2013

Background

Hypertension is an important modifiable risk factor for coronary heart disease, congestive heart failure, stroke, end-stage renal disease, and peripheral vascular disease. Many of the molecular mechanisms and genetic factors underlying the development of the most common forms of human hypertension remain to be defined. Nitric oxide (NO) and one of its primary targets, the cyclic guanosine monophosphate (cGMP) generating enzyme soluble guanylate cyclase (sGC), play an essential role in regulating blood pressure, in part by by modulating relaxation of vascular smooth muscle.

Results

Male mice deficient in the α1 subunit of soluble guanylate cyclase (sGCα1-/- mice) are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension associated with sGCα1-deficiency. Using linkage analyses, we discovered quantitative trait loci (QTL) that were linked to mean arterial pressure (MAP) in sGCα1-/- mice. One locus is syntenic with previously identified blood pressure–related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension in sGCα1-/- mice was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS) and RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα1-/- mice.

Conclusion

These data identify the RAAS as a blood pressure–modifying mechanism in a setting of impaired NO/cGMP signaling [1].

Authors’ Affiliations

(1)
Anesthesia Center for Critical Care Research Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School

References

  1. Buys ES, Raher MJ, Kirby A, Mohd S, Baron DM, Hayton SR, Tainsh LT, Sips PY, Rauwerdink KM, Yan Q, Tainsh RET, Shakartzi HR, Stevens C, Decaluwé K, Rodrigues-Machado MDG, Malhotra R, Van de Voorde J, Wang T, Brouckaert P, Daly MJ, Bloch KD: Genetic modifiers of hypertension in soluble guanylate cyclase α1-deficient mice. J Clin Invest. 2012, 122: 2316-2325. 10.1172/JCI60119.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Buys; licensee BioMed Central Ltd. 2013

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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