{
    "abstract": "Soluble guanylate cyclase (sGC) stands as a pivotal regulatory element in intracellular signalling pathways, mediating the formation of cyclic guanosine monophosphate (cGMP) and impacting diverse physiological processes across tissues. Increased formation of reactive oxygen species (ROS) is widely recognized to modulate cGMP signalling. Indeed, oxidatively damaged, and therefore inactive sGC, contributes to poor vascular reactivity and more severe neurological damage upon stroke. However, the specific involvement of cGMP in redox signalling remains elusive. Here, we demonstrate a significant cGMP-dependent reduction of reactive oxygen and nitrogen species upon sGC activation under hypoxic conditions, independent of any potential scavenger effects. Importantly, this reduction is directly mediated by downregulating NADPH oxidase (NOX) 4 and 5 during reperfusion. Using an in silico simulation approach, we propose a mechanistic link between increased cGMP signalling and reduced ROS formation, pinpointing NF-\u03baB1 and RELA/p65 as key transcription factors regulating NOX4/5 expression. In vitro studies revealed that p65 translocation to the nucleus was reduced in hypoxic human microvascular endothelial cells following sGC activation. Altogether, these findings unveil the intricate regulation and functional implications of sGC, providing valuable insights into its biological significance and ultimately therapeutic potential.",
    "authors": [
        {
            "affiliation": "Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copengagen 2200, Denmark; Department of Mathematics and Computer Science, University of Southern Denmark, Odense 5230, Denmark.",
            "firstname": "Alexander G",
            "initials": "AG",
            "lastname": "Gr\u00f8nning"
        },
        {
            "affiliation": "Department of Neurology and Center for Translational Neuro, and Behavioural Sciences (C-TNBS), Department of Neurology, University Hospital Essen, Essen 45147, Germany.",
            "firstname": "Sebastian E",
            "initials": "SE",
            "lastname": "Vonhof"
        },
        {
            "affiliation": "Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt; Department of Pharmacology & Personalised Medicine, MeHNS, Faculty of Health, Medicine & Life Science, Maastricht University, Maastricht, ER 6229, the Netherlands.",
            "firstname": "Mahmoud",
            "initials": "M",
            "lastname": "Elbatreek"
        },
        {
            "affiliation": "Department of Neurology and Center for Translational Neuro, and Behavioural Sciences (C-TNBS), Department of Neurology, University Hospital Essen, Essen 45147, Germany.",
            "firstname": "Anna",
            "initials": "A",
            "lastname": "Hamker"
        },
        {
            "affiliation": "Department of Neurology and Center for Translational Neuro, and Behavioural Sciences (C-TNBS), Department of Neurology, University Hospital Essen, Essen 45147, Germany.",
            "firstname": "Rebecca D",
            "initials": "RD",
            "lastname": "Szepanowski"
        },
        {
            "affiliation": "Department of Neurology and Center for Translational Neuro, and Behavioural Sciences (C-TNBS), Department of Neurology, University Hospital Essen, Essen 45147, Germany.",
            "firstname": "Svenja C",
            "initials": "SC",
            "lastname": "Erkelenz"
        },
        {
            "affiliation": "Department of Neurology and Center for Translational Neuro, and Behavioural Sciences (C-TNBS), Department of Neurology, University Hospital Essen, Essen 45147, Germany.",
            "firstname": "Friederike",
            "initials": "F",
            "lastname": "Langhauser"
        },
        {
            "affiliation": "Instituto de Investigaci\u00f3n Sanitaria, Servicio de Farmacolog\u00eda Cl\u00ednica, Hospital Universitario de la Princesa, Madrid 28006, Spain.",
            "firstname": "Javier",
            "initials": "J",
            "lastname": "Egea"
        },
        {
            "affiliation": "Instituto de I+D del Medicamento Te\u00f3filo Hernando (ITH), Departamento de Farmacolog\u00eda, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Madrid 28029, Spain.",
            "firstname": "Manuela G",
            "initials": "MG",
            "lastname": "Lopez"
        },
        {
            "affiliation": "Department of Mathematics and Computer Science, University of Southern Denmark, Odense 5230, Denmark; Institute for Computational Systems Biology, University of Hamburg, Hamburg 22761, Germany.",
            "firstname": "Jan",
            "initials": "J",
            "lastname": "Baumbach"
        },
        {
            "affiliation": "Department of Neurology and Center for Translational Neuro, and Behavioural Sciences (C-TNBS), Department of Neurology, University Hospital Essen, Essen 45147, Germany.",
            "firstname": "Christoph",
            "initials": "C",
            "lastname": "Kleinschnitz"
        },
        {
            "affiliation": "Department of Neurology and Center for Translational Neuro, and Behavioural Sciences (C-TNBS), Department of Neurology, University Hospital Essen, Essen 45147, Germany; Department of Pharmacology & Personalised Medicine, MeHNS, Faculty of Health, Medicine & Life Science, Maastricht University, Maastricht, ER 6229, the Netherlands. Electronic address: anaisabel.casasguijarro@uk-essen.de.",
            "firstname": "Ana I",
            "initials": "AI",
            "lastname": "Casas"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.",
    "doi": "10.1016/j.biopha.2025.117829",
    "journal": "Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie",
    "keywords": [
        "Brain ischemia",
        "NADPH oxidase",
        "Redox signalling",
        "Soluble guanylate cyclase",
        "cGMP"
    ],
    "methods": null,
    "publication_date": "2025-01-15",
    "pubmed_id": "39809128",
    "results": null,
    "title": "Unveiling the interplay between soluble guanylate cyclase activation and redox signalling in stroke pathophysiology and treatment.",
    "xml": "<Element 'PubmedArticle' at 0x788505bea020>"
}