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Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury.

ABSTRACT: Nitric oxide mediates endothelium-dependent vasodilation, modulates cerebral blood flow, and determines stroke outcome. Nitric oxide signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To study the role of sGC in stroke injury, we compared the outcome of cerebral ischemia and reperfusion in mice deficient in the alpha(1) subunit of sGC (sGCalpha(1)(-/-)) with that in wild-type mice.Blood pressure, cerebrovascular anatomy, and vasoreactivity of pressurized carotid arteries were compared in both mouse genotypes. Cerebral blood flow was measured before and during middle cerebral artery occlusion and reperfusion. We then assessed neurological deficit and infarct volume after 1 hour of occlusion and 23 hours of reperfusion and after 24 hours of occlusion.Blood pressure and cerebrovascular anatomy were similar between genotypes. We found that vasodilation of carotid arteries in response to acetylcholine or sodium nitroprusside was diminished in sGCalpha(1)(-/-) compared with wild-type mice. Cerebral blood flow deficits did not differ between the genotypes during occlusion, but during reperfusion, cerebral blood flow was 45% less in sGCalpha(1)(-/-) mice. Infarct volumes and neurological deficits were similar after 24 hours of occlusion in both genotypes. After 1 hour of ischemia and 23 hours of reperfusion, infarct volumes were 2-fold larger and neurological deficits were worse in sGCalpha(1)(-/-) than in the wild-type mice.sGCalpha(1) deficiency impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse neurological damage, suggesting that cGMP generated by sGCalpha(1)beta(1) is protective in ischemic stroke.

SUBMITTER: Atochin DN

PROVIDER: S-EPMC3047459 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury.

Atochin Dmitriy N DN Yuzawa Izumi I Li Qian Q Rauwerdink Kristen M KM Malhotra Rajeev R Chang Junlei J Brouckaert Peter P Ayata Cenk C Moskowitz Michael A MA Bloch Kenneth D KD Huang Paul L PL Buys Emmanuel S ES

Stroke 20100701 8

<h4>Background and purpose</h4>Nitric oxide mediates endothelium-dependent vasodilation, modulates cerebral blood flow, and determines stroke outcome. Nitric oxide signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To study the role of sGC in stroke injury, we compared the outcome of cerebral ischemia and reperfusion in mice deficient in the alpha(1) subunit of sGC (sGCalpha(1)(-/-)) with that in wild-type mice.<h4>Methods</h4>Blood pressure, cerebrovascular anato ...[more]

PMID: 20595671

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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 ?1 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 ?1 H-NOX construct (residues 1-194), the ?1 H-NOX-PAS-CC construct (residues 1-385), and the full-length ?1?1 sGC heterodimer (?1 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.

Dataset Information

Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury.

Publications

Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury.

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