Thoonen, RobrechtCauwels, AnjeDecaluwe, KellyGeschka, SandraTainsh, RobertDelanghe, JorisHochepied, TinoDe Cauwer, LodeRogge, ElkeVoet, SofieSips, PatrickKaras, Richard H.Bloch, KennethVuylsteke, MarnikStasch, Johannes-PeterVan de Voorde, JohanBuys, EmmanuelBrouckaert, Peter2016-12-212015Thoonen, Robrecht, Anje Cauwels, Kelly Decaluwe, Sandra Geschka, Robert E. Tainsh, Joris Delanghe, Tino Hochepied, et al. 2015. Cardiovascular and Pharmacological Implications of Haem-Deficient NO-Unresponsive Soluble Guanylate Cyclase Knock-in Mice. Nature Communications 6: 8482. doi:10.1038/ncomms9482.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:29729414Oxidative 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.en-USJournal Article2016-12-2110.1038/ncomms9482