Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice
De Cauwer, Lode
Karas, Richard H.
Van de Voorde, Johan
Brouckaert, PeterNote: Order does not necessarily reflect citation order of authors.
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CitationThoonen, 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.
AbstractOxidative 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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