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Nat Commun. 2015 Oct 7;6:8482. doi: 10.1038/ncomms9482.

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

Author information

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.

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.

PMID:
26442659
PMCID:
PMC4699393
DOI:
10.1038/ncomms9482
[Indexed for MEDLINE]
Free PMC Article

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