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
  • 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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