1. Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice
- Author
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Emmanuel S, Buys, Michael J, Raher, Andrew, Kirby, Mohd, Shahid, Shahid, Mohd, David M, Baron, Sarah R, Hayton, Laurel T, Tainsh, Patrick Y, Sips, Kristen M, Rauwerdink, Qingshang, Yan, Robert E T, Tainsh, Hannah R, Shakartzi, Christine, Stevens, Kelly, Decaluwé, Maria da Gloria, Rodrigues-Machado, Rajeev, Malhotra, Johan, Van de Voorde, Tong, Wang, Peter, Brouckaert, Mark J, Daly, and Kenneth D, Bloch
- Subjects
Male ,Vascular smooth muscle ,TGR(MREN2) 27 RATS ,Genetic Linkage ,SMOOTH-MUSCLE-CELLS ,CONVERTING ENZYME ,Receptors, Cytoplasmic and Nuclear ,Vasodilation ,Second Messenger Systems ,Renin-Angiotensin System ,Mice ,chemistry.chemical_compound ,Soluble Guanylyl Cyclase ,Renin ,Cyclic GMP ,Mice, Knockout ,QUANTITATIVE TRAIT LOCI ,BLOOD-PRESSURE REGULATION ,General Medicine ,Nitric oxide synthase ,RENIN-ANGIOTENSIN SYSTEM ,Hypertension ,Knockout mouse ,Female ,Corrigendum ,Research Article ,medicine.medical_specialty ,Quantitative Trait Loci ,Context (language use) ,Biology ,Quantitative trait locus ,Nitric oxide ,Species Specificity ,Internal medicine ,Renin–angiotensin system ,medicine ,Animals ,Humans ,GENOME-WIDE ASSOCIATION ,NITRIC-OXIDE SYNTHASE ,Genome, Human ,Biology and Life Sciences ,KIDNEY-DISEASE ,Rats ,Endocrinology ,chemistry ,Guanylate Cyclase ,biology.protein ,Endothelium, Vascular ,KNOCKOUT MICE - Abstract
Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα1), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα1 deficiency. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα1-deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling.
- Published
- 2012
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