Many important physiological processes, such as vasodilation and neurotransmission, are mediated by nitric oxide (NO) signaling.  Soluble guanylate cyclase (sGC) is the primary receptor for NO. NO binding to the ferrous (Fe2+) heme cofactor activates sGC which mediates the downstream effects of NO.  Under oxidative stress, sGC heme can be oxidized resulting in NO insensitivity; currently the fate of oxidized sGC is unknown.  Cinaciguat has been developed to activate oxidized enzyme, but the mechanism of activation by cinaciguat remains elusive.  Here, the stability of oxidized sGC was investigated by monitoring the rate of heme loss, and the mechanism of action of cinaciguat was investigated by its effects on heme dissociation.  Cinaciguat interaction with oxidized sGC lead to faster heme dissociation showing that cinaciguat directly interacts with the oxidized enzyme. In conclusion, oxidized sGC is prone to heme loss, and cinaciguat reactivates oxidized sGC by displacement of ferric heme.

Activation of soluble guanylate cyclase with cinaciguat

243rd National Meeting (2012)

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