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Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in
Robrecht Thoonen1,2, Anje Cauwels1,2, Kelly Decaluwe3
1Laboratory for Molecular Pathology and Experimental Therapy, Inflammation Research Center, VIB, B-9052 Ghent, Belgium.
Insights
Oxidative stress impairs cardiovascular function by affecting soluble guanylate cyclase (sGC). New Apo-sGC mice, lacking haem-sGC, reveal nitric oxide (NO) pathways and highlight the therapeutic potential of sGC activators.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Pharmacology
Background:
- Oxidative stress is a key factor in cardiovascular disease, leading to the loss of the haem group in soluble guanylate cyclase (sGC). This loss prevents activation by nitric oxide (NO).
- Understanding the specific roles of sGC in NO signaling is crucial for developing effective cardiovascular therapies.
Purpose of the Study:
- To investigate the in vivo consequences of haem-free sGC and differentiate between sGC-dependent and -independent NO effects.
- To evaluate the therapeutic potential of sGC activators in a model with impaired NO signaling.
Main Methods:
- Generation of Apo-sGC mice expressing haem-free sGC.
- Assessment of haemodynamic responses to NO and the sGC activator cinaciguat.
- Evaluation of TNF-induced hypotension and mortality in Apo-sGC mice.
Main Results:
- Apo-sGC mice are viable and develop hypertension, with abolished haemodynamic effects of NO but enhanced effects of cinaciguat.
- NO-mediated smooth muscle relaxation, blood pressure regulation, and platelet aggregation inhibition require sGC activation by NO.
- Cardiovascular collapse in shock, induced by TNF, is preserved in Apo-sGC mice, indicating non-sGC signaling pathways.
Conclusions:
- Apo-sGC mice provide a novel platform to study sGC oxidation and NO signaling in vivo.
- These mice enable the distinction between haem-dependent and -independent sGC functions.
- The findings support the therapeutic strategy of using sGC activators for cardiovascular conditions.
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.
