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

Robrecht Thoonen, Anje Cauwels, Kelly Decaluwe, Sandra Geschka, Robert E Tainsh, Joris Delanghe, Tino Hochepied, Lode De Cauwer, Elke Rogge, Sofie Voet, Patrick Sips, Richard H Karas, Kenneth D Bloch, Marnik Vuylsteke, Johannes-Peter Stasch, Johan Van de Voorde, Emmanuel S Buys, Peter Brouckaert

Index: Nat. Commun. 6 , 8482, (2015)

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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.