Dataset Information

Genetic modifiers of hypertension in soluble guanylate cyclase ?1-deficient 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 ?1 subunit of soluble guanylate cyclase (sGC?1), 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 sGC?1 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 sGC?1-deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling.

SUBMITTER: Buys ES

PROVIDER: S-EPMC3366402 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Genetic modifiers of hypertension in soluble guanylate cyclase α1-deficient mice.

Buys Emmanuel S ES Raher Michael J MJ Kirby Andrew A Shahid Mohd M Baron David M DM Hayton Sarah R SR Tainsh Laurel T LT Sips Patrick Y PY Rauwerdink Kristen M KM Yan Qingshang Q Tainsh Robert E T RE Shakartzi Hannah R HR Stevens Christine C Decaluwé Kelly K Rodrigues-Machado Maria da Gloria Mda G Malhotra Rajeev R Van de Voorde Johan J Wang Tong T Brouckaert Peter P Daly Mark J MJ Bloch Kenneth D KD

The Journal of clinical investigation 20120508 6

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 arteria ...[more]

PMID: 22565307

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Project description:Background: Lower-limb peripheral artery disease (PAD) is one of the major complications of diabetes mellitus. PAD is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the PAD population. Praliciguat is an orally available soluble guanylate cyclase (sGC) stimulator that has been reported both pre-clinically and in early-stage clinical trials to have favorable effects in metabolic and hemodynamic outcomes, suggesting that it may have a potential beneficial effect in PAD. Objective: We evaluated the effect of praliciguat on hind limb ischemia (HLI) recovery in a mouse model of type 2 diabetes. Methods: HLI was induced in leptin receptor-deficient (Leprdb/db) mice by ligation and excision of the left femoral artery. Praliciguat (10 mg/kg/day) was administered in the diet starting 3 days before surgery. Results: 28 days after surgery, ischemic foot perfusion and function parameters were better in praliciguat-treated mice than in vehicle controls. Improved ischemic foot perfusion was not associated with either improved traditional cardiovascular risk factors (i.e., weight, glycemia) or increased angiogenesis. However, treatment with praliciguat significantly increased arteriole diameter, decreased intercellular adhesion molecule 1 (ICAM1) expression, and prevented the accumulation of oxidative pro-angiogenic and pro-inflammatory muscle fibers. While investigating the mechanism underlying the beneficial effects of praliciguat therapy, we found that praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression in cultured myoblasts and that conditioned medium form praliciguat-treated myoblast decreased ICAM-1 mRNA expression in endothelial cells. These results suggest that praliciguat therapy may decrease ICAM-1 expression in endothelial cells by downregulating Cxcl12 in myocytes. Conclusion: Our results demonstrated that praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM-1 expression.

Dataset Information

Genetic modifiers of hypertension in soluble guanylate cyclase ?1-deficient mice.

Publications

Genetic modifiers of hypertension in soluble guanylate cyclase α1-deficient mice.

Similar Datasets

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