title: Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice.
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.
authors.affiliation: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Robrecht
authors.initials: R
authors.lastname: Thoonen
authors.affiliation: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Anje
authors.initials: A
authors.lastname: Cauwels
authors.affiliation: Department of Pharmacology, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Decaluwe
authors.affiliation: Cardiovascular Research, Bayer Pharma AG, D-42096 Wuppertal, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Geschka
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Tainsh
authors.affiliation: Department of Clinical Biology, Ghent University Hospital, B-9000 Ghent, Belgium.
authors.forename: Joris
authors.initials: J
authors.lastname: Delanghe
authors.affiliation: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Tino
authors.initials: T
authors.lastname: Hochepied
authors.affiliation: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Lode
authors.initials: L
authors.lastname: De Cauwer
authors.affiliation: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Elke
authors.initials: E
authors.lastname: Rogge
authors.affiliation: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Voet
authors.affiliation: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sips
authors.affiliation: Molecular Cardiology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Boston Massachusetts 02111, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.affiliation: Department of Plant Systems Biology, VIB, B-9052 Ghent, Belgium.|Department of Plant Biotechnology and Genetics, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Marnik
authors.initials: M
authors.lastname: Vuylsteke
authors.affiliation: Cardiovascular Research, Bayer Pharma AG, D-42096 Wuppertal, Germany.|Department of Pharmacology, The School of Pharmacy, Martin-Luther-University, Halle, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.affiliation: Department of Pharmacology, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Van de Voorde
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute, Boston, Massachusetts 02114, USA.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.affiliation: Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006162:Guanylate Cyclase / Q000235:genetics*; D006418:Heme / Q000235:genetics*; D006973:Hypertension / Q000235:genetics; D007022:Hypotension / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D000071756:Soluble Guanylyl Cyclase; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001565:Benzoates; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C480588:BAY 58-2667; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase