Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels
Johannes-Peter Stasch, … , Werner Müller-Esterl, Harald H.H.W. Schmidt
Johannes-Peter Stasch, … , Werner Müller-Esterl, Harald H.H.W. Schmidt
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2552-2561. https://doi.org/10.1172/JCI28371.
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Research Article Cardiology

Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels

Abstract

ROS are a risk factor of several cardiovascular disorders and interfere with NO/soluble guanylyl cyclase/cyclic GMP (NO/sGC/cGMP) signaling through scavenging of NO and formation of the strong oxidant peroxynitrite. Increased oxidative stress affects the heme-containing NO receptor sGC by both decreasing its expression levels and impairing NO-induced activation, making vasodilator therapy with NO donors less effective. Here we show in vivo that oxidative stress and related vascular disease states, including human diabetes mellitus, led to an sGC that was indistinguishable from the in vitro oxidized/heme-free enzyme. This sGC variant represents what we believe to be a novel cGMP signaling entity that is unresponsive to NO and prone to degradation. Whereas high-affinity ligands for the unoccupied heme pocket of sGC such as zinc–protoporphyrin IX and the novel NO-independent sGC activator 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino) methyl [benzoic]acid (BAY 58-2667) stabilized the enzyme, only the latter activated the NO-insensitive sGC variant. Importantly, in isolated cells, in blood vessels, and in vivo, BAY 58-2667 was more effective and potentiated under pathophysiological and oxidative stress conditions. This therapeutic principle preferentially dilates diseased versus normal blood vessels and may have far-reaching implications for the currently investigated clinical use of BAY 58-2667 as a unique diagnostic tool and highly innovative vascular therapy.

Authors

Johannes-Peter Stasch, Peter M. Schmidt, Pavel I. Nedvetsky, Tatiana Y. Nedvetskaya, Arun Kumar H.S., Sabine Meurer, Martin Deile, Ashraf Taye, Andreas Knorr, Harald Lapp, Helmut Müller, Yagmur Turgay, Christiane Rothkegel, Adrian Tersteegen, Barbara Kemp-Harper, Werner Müller-Esterl, Harald H.H.W. Schmidt

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Figure 7

NO receptor sGC exists in a physiological equilibrium between 2 redox states, the reduced and NO-sensitive versus the oxidized and heme mimetic–sensitive form.

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NO receptor sGC exists in a physiological equilibrium between 2 redox st...
Under pathophysiological conditions, this relative ratio is shifted toward the oxidized form, which is selectively targeted by sGC activators such as BAY 58-2667 to overcome the pathophysiology of impaired NO-cGMP signaling. In addition, high-affinity heme-site ligands such as Zn-PPIX (Zn) or BAY 58-2667 (BAY) are able to block the oxidation-accelerated degradation of the sGC α/β heterodimer, thereby stabilizing and conserving the enzyme protein levels in an inactive (Zn-PPIX–bound) or active (BAY 58-2667–bound) form even under oxidizing conditions. Furthermore, heme-site ligands decelerate the physiological turnover of the sGC β subunit, resulting in an accumulation of this monomeric protein.