2. Academic Validation
  3. Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice

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

  • Nat Commun. 2015 Oct 7;6:8482. doi: 10.1038/ncomms9482.
Robrecht Thoonen 1 2,  Anje Cauwels 1 2,  Kelly Decaluwe 3,  Sandra Geschka 4,  Robert E Tainsh 5,  Joris Delanghe 6,  Tino Hochepied 1 2,  Lode De Cauwer 1 2,  Elke Rogge 1 2,  Sofie Voet 1 2,  Patrick Sips 1 2,  Richard H Karas 7,  Kenneth D Bloch 5,  Marnik Vuylsteke 8 9,  Johannes-Peter Stasch 4 10,  Johan Van de Voorde 3,  Emmanuel S Buys 5,  Peter Brouckaert 1 2
Affiliations

Affiliations

  • 1 Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.
  • 2 Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
  • 3 Department of Pharmacology, Ghent University, B-9000 Ghent, Belgium.
  • 4 Cardiovascular Research, Bayer Pharma AG, D-42096 Wuppertal, Germany.
  • 5 Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, USA.
  • 6 Department of Clinical Biology, Ghent University Hospital, B-9000 Ghent, Belgium.
  • 7 Molecular Cardiology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston Massachusetts 02111, USA.
  • 8 Department of Plant Systems Biology, VIB, B-9052 Ghent, Belgium.
  • 9 Department of Plant Biotechnology and Genetics, Ghent University, B-9052 Ghent, Belgium.
  • 10 Department of Pharmacology, The School of Pharmacy, Martin-Luther-University, Halle, Germany.
PMID: 26442659 DOI: 10.1038/ncomms9482
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.

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