Abstract 13076: Genetic Mapping of a Modifier Locus Affecting Blood Pressure in Soluble Guanylate Cyclase α1-Deficient Mice.
Background We previously reported that male mice deficient in the a1 subunit of the nitric oxide receptor soluble guanylate cyclase (sGCa1-/- mice) are hypertensive. The phenotype depends on the genetic background: sGCa1-/- mice on a 129S6 (S6) background (sGCa1-/-S6) but not on a C57BL/6 (B6) background (sGCa1-/-B6) develop hypertension. Because these findings suggest that hypertension associated with sGCa1-deficiency is modulated by genetic factors, we sought to identify modifier genes of blood pressure in sGCa1-/-S6 mice.
Methods and Results Mean arterial blood pressure (MAP) of 284 male F2 offspring from a sGCa1-/-S6 X sGCa1-/-B6 cross varied between values observed in parental sGCa1-/-S6 and sGCa1-/-B6 mice. Linkage analysis using MAPMAKER/QTL revealed a quantitative trait locus (QTL) on chromosome 1 associated with blood pressure. This region is syntenic with previously identified hypertension-related QTLs in the human and rat genomes and contains the renin genes. 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 with elevated MAP in the F2 mice (P<0.001). Plasma renin activity and aldosterone levels were higher in sGCa1-/-S6 than in WTS6 mice. Inhibiting the renin-angiotensin-aldosterone system (RAAS), either by treatment with the renin inhibitor, Aliskiren, or the aldosterone antagonist, Spironolactone, normalized blood pressure in sGCa1-/-S6 mice. Renal clearance studies did not reveal renal dysfunction in sGCa1-/-S6 mice. Aortic ring studies confirmed that the response to acetylcholine is impaired to a greater extent in sGCa1-/-S6 than in sGCa1-/-B6 mice. Pre-treating sGCa1-/-S6 mice with Enalapril restored vascular reactivity in sGCa1-/-S6 mice to the level observed in sGCa1-/-B6 mice.
Conclusions These data identify renin as a genetic modifier of blood pressure in a setting of impaired NO-cGMP signaling and suggest that increased activity of the RAAS mediates the greater impairment of vascular reactivity in sGCa1-/-S6 than in sGCa1-/-B6 mice. Together, these findings highlight the importance of sGC in the regulation of the RAAS and suggest that sGC may be a therapeutic target in RAAS-dependent hypertension.
- © 2011 by American Heart Association, Inc.