Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice

Robrecht Thoonen (), Anje Cauwels, Kelly Decaluwe, Sandra Geschka, Robert E. Tainsh, Joris Delanghe, Tino Hochepied, Lode De Cauwer, Elke Rogge, Sofie Voet, Patrick Sips, Richard H. Karas, Kenneth D. Bloch, Marnik Vuylsteke, Johannes-Peter Stasch, Johan Van de Voorde, Emmanuel S. Buys and Peter Brouckaert ()
Additional contact information
Robrecht Thoonen: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center
Anje Cauwels: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center
Kelly Decaluwe: Ghent University
Sandra Geschka: Cardiovascular Research, Bayer Pharma AG
Robert E. Tainsh: Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute
Joris Delanghe: Ghent University Hospital
Tino Hochepied: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center
Lode De Cauwer: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center
Elke Rogge: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center
Sofie Voet: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center
Patrick Sips: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center
Richard H. Karas: Molecular Cardiology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center
Kenneth D. Bloch: Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute
Marnik Vuylsteke: Department of Plant Systems Biology
Johannes-Peter Stasch: Cardiovascular Research, Bayer Pharma AG
Johan Van de Voorde: Ghent University
Emmanuel S. Buys: Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute
Peter Brouckaert: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators.

Date: 2015
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DOI: 10.1038/ncomms9482

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