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Stimulation of soluble guanylate cyclase exerts anti-inflammatory actions in the liver through a VASP/NF-kB/NLRP3 inflammasome circuit

ABSTRACT: Stimulation of soluble guanylate cyclase exerts anti-inflammatory actions in the liver through a VASP/NF-kB/NLRP3 inflammasome circuit

PROVIDER: PRJNA647837 | ENA |

REPOSITORIES: ENA

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Stimulation of soluble guanylate cyclase exerts anti-inflammatory actions in the liver through a VASP/NF-kB/NLRP3 inflammasome circuit

Project description:Soluble guanylate cyclase (sGC) catalyzes the conversion of GTP into cyclic guanosine-3',5’-monophosphate (cGMP), a key second messenger in cell signaling and tissue homeostasis. We and others recently demonstrated that sGC stimulation is associated with a remarkable anti-inflammatory effect in the liver of mice experimentally induced to nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms of action underlying the anti-inflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted anti-inflammatory and anti-fibrotic actions in mice fed with choline-deficient L-amino acid-defined high-fat diet (CDAHFD), an optimized experimental model of NASH. The anti-inflammatory effect of PRL was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL anti-inflammatory effect was also associated with a remarkable suppression of hepatic levels of IL-1β, NLPR3, ASC and active cleaved-Caspase-1, which are components of the NLRP3 inflammasome. In vitro, in Kupffer cells challenged with the classical inflammasome model of LPS plus ATP, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the PKG-mediated phosphorylation of the VASP Ser239 residue, which in turn, reduced NF- κB activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-Caspase-1 levels independently of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts anti-inflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-kB/NLRP3 inflammasome circuit.

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Expression Profiling: Guanylate Cyclase Soluble Subunit Beta-3 (GUCY1B3) overexpression U87 MG cells

Project description:Total RNA were extracted from Guanylate Cyclase Soluble Subunit Beta-3 (GUCY1B3) overexpression U87 MG stable cell lines and U87 MG cells. Three RNA samples of each of the two cell lines were used for microarray analysis to compare gene expression profile Guanylate Cyclase Soluble Subunit Beta-3 (GUCY1B3) was cloned into pCDNA3.1D/V5-His-TOPO plasmid (Invitrgen) and then transfected into U87 MG (ATCC HTB-1) cells to generate stable overexpression cells. RNA from the stable cell lines and U87 MG were used for microarray

2016-06-15 | E-GEOD-83344 | biostudies-arrayexpress

Expression Profiling: Guanylate Cyclase Soluble Subunit Beta-3 (GUCY1B3) overexpression U87 MG cells

2016-06-15 | GSE83344 | GEO

The soluble guanylate cyclase CYG12 is required for the acclimation to hypoxia and trophic regimes in Chlamydomonas reinhardtii

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Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit.

Project description:Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3',5'-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit.

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Soluble Guanylate Cyclase Signalling Mediates Etoposide Resistance in Progressing Small Cell Lung Cancer

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Treatment effects of soluble guanylate cyclase modulation on diabetic kidney disease at single-cell resolution

Project description:Diabetic kidney disease (DKD) is the most common cause of renal failure. Therapeutics development is hampered by our incomplete understanding of animal models on a cellular level. We show that ZSF1 rats recapitulate human DKD on a phenotypic and transcriptomic level. Tensor decomposition prioritizes proximal tubule (PT) and stroma as phenotype-relevant cell types exhibiting a continuous lineage relationship. As DKD features endothelial dysfunction, oxidative stress, and nitric oxide depletion, soluble guanylate cyclase (sGC) is a promising DKD drug target. sGC expression is specifically enriched in PT and stroma. In ZSF1 rats, pharmacological sGC activation confers considerable benefits over stimulation and is mechanistically related to improved oxidative stress regulation, resulting in enhanced downstream cGMP effects. Finally, we define sGC gene co-expression modules, which allow stratification of human kidney samples by DKD prevalence and disease-relevant measures such as kidney function, proteinuria, and fibrosis, underscoring the relevance of the sGC pathway to patients.

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Loss of soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia.

Project description:Background: Moyamoya is a cerebrovascular condition of unknown mechanism characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICA) and the compensatory development of abnormal “moyamoya” vessels. It leads to ischemic and hemorrhagic stroke. We describe a novel autosomal recessive disease leading to severe moyamoya and early onset achalasia and report its cause in 3 unrelated families. Methods: We used a combination of genetic linkage and exome sequencing in 2 consanguineous to identify rare shared variants. Sanger sequencing of GUCY1A3, the sole gene mutated in both families, was then conducted in the third family. Platelets from one of the patients and controls were used to carry out functional studies. Results: Homozygous mutations of GUCY1A3 gene encoding the alpha1 subunit of soluble guanylate cyclase (sGC), the major receptor for Nitric Oxide (NO), were identified in all 3 families. Platelet analysis showed a complete loss of the mutated protein and showed an unexpected stimulatory role of sGC within platelets. Conclusion: The NO/sGC/cGMP pathway is a major pathway controlling vascular smooth muscle (VSMC) relaxation, vascular tone and vascular remodeling. Our data suggest that alterations of this pathway may lead to an abnormal vascular remodeling process in sensitive vascular areas with low blood

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The soluble guanylate cyclase stimulator praliciguat promotes ischemic leg reperfusion in leptin receptor-deficient mice

Project description:The soluble guanylate cyclase stimulator praliciguat promotes ischemic leg reperfusion in leptin receptor-deficient mice

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Treatment effects of soluble guanylate cyclase modulation on diabetic kidney disease at single-cell resolution

Project description:Treatment effects of soluble guanylate cyclase modulation on diabetic kidney disease at single-cell resolution

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