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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 The tyrosine kinase inhibitor sunitinib causes hypertension associated with reduced nitric oxide (NO) availability, elevated renal vascular resistance, and decreased fractional sodium excretion. We tested whether (1) nitrate supplementation mitigates sunitinib-induced hypertension and NO contributes less to renal vascular resistance as well as fractional sodium excretion regulation in sunitinib-treated rats than in controls; and (2) renal soluble guanylate cyclase (sGC) is downregulated and sGC activation lowers arterial pressure in rats with sunitinib-induced hypertension. Methods and Results Arterial pressure responses to nitrate supplementation and the effects of systemic and intrarenal NO synthase (NOS) inhibition on renal hemodynamics and fractional sodium excretion were assessed in sunitinib-treated rats and controls. Renal NOS and sGC mRNA as well as protein abundances were determined by quantitative polymerase chain reaction and Western blot. The effect of the sGC activator cinaciguat on arterial pressure was investigated in sunitinib-treated rats. Nitrate supplementation did not mitigate sunitinib-induced hypertension. Endothelium-dependent reductions in renal vascular resistance were similar in control and sunitinib-treated animals without and with systemic NOS inhibition. Selective intrarenal NOS inhibition lowered renal medullary blood flow in control but not in sunitinib-treated rats without significant effects on fractional sodium excretion. Renal cortical sGC mRNA and sGC α1-subunit protein abundance were less in sunitinib-treated rats than in controls, and cinaciguat effectively lowered arterial pressure by 15-20 mm Hg in sunitinib-treated rats. Conclusions Renal cortical sGC is downregulated in the presence of intact endothelium-dependent renal vascular resistance regulation in developing sunitinib-induced hypertension. This suggests that sGC downregulation occurs outside the renal vasculature, increases renal sodium retention, and contributes to nitrate resistance of sunitinib-induced hypertension.

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.

Project description:Eukaryotic nitric oxide (NO) signaling involves modulation of cyclic GMP (cGMP) levels through activation of the soluble isoform of guanylate cyclase (sGC). sGC is a heterodimeric hemoprotein that contains a Heme-Nitric oxide and OXygen binding (H-NOX) domain, a Per/ARNT/Sim (PAS) domain, a coiled-coil (CC) domain, and a catalytic domain. To evaluate the role of these domains in regulating the ligand binding properties of the heme cofactor of NO-sensitive sGC, we constructed chimeras by swapping the rat β1 H-NOX domain with the homologous region of H-NOX domain-containing proteins from Thermoanaerobacter tengcongensis, Vibrio cholerae, and Caenorhabditis elegans (TtTar4H, VCA0720, and Gcy-33, respectively). Characterization of ligand binding by electronic absorption and resonance Raman spectroscopy indicates that the other rat sGC domains influence the bacterial and worm H-NOX domains. Analysis of cGMP production in these proteins reveals that the chimeras containing bacterial H-NOX domains exhibit guanylate cyclase activity, but this activity is not influenced by gaseous ligand binding to the heme cofactor. The rat-worm chimera containing the atypical sGC Gcy-33 H-NOX domain was weakly activated by NO, CO, and O(2), suggesting that atypical guanylate cyclases and NO-sensitive guanylate cyclases have a common molecular mechanism for enzyme activation. To probe the influence of the other sGC domains on the mammalian sGC heme environment, we generated heme pocket mutants (Pro118Ala and Ile145Tyr) in the β1 H-NOX construct (residues 1-194), the β1 H-NOX-PAS-CC construct (residues 1-385), and the full-length α1β1 sGC heterodimer (β1 residues 1-619). Spectroscopic characterization of these proteins shows that interdomain communication modulates the coordination state of the heme-NO complex and the heme oxidation rate. Taken together, these findings have important implications for the allosteric mechanism of regulation within H-NOX domain-containing proteins.

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

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

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