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 3

Effects of oxidative agents on BAY 58-2667–induced cGMP accumulation in native cells.

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Effects of oxidative agents on BAY 58-2667–induced cGMP accumulation in ...
(A) Basal (white bars) and BAY 58-2667–stimulated (black bars) cGMP accumulation were measured in untreated (control) porcine pulmonary artery endothelial cells and cells treated for 30 minutes with 20 μM ODQ. (B) Basal and BAY 58-2667–stimulated cGMP accumulation was measured in untreated (white bars) human platelets and human platelets treated with ODQ for 30 minutes (black bars). Basal cGMP level was 0.15 ± 0.01 pmol/106 cells. (C) Basal, 250 μM DEA/NO–stimulated, and 10 μM BAY 58-2667–stimulated cGMP accumulation was measured in untreated (white bars) endothelial cells and cells treated with 500 μM SIN-1 for 24 hours (black bars). Basal cGMP level was 0.16 ± 0.04 pmol/106 cells. Data are means ± SEM of 3 independent experiments performed in triplicate. (D) cGMP content of aortic rings of Wistar rats and SHR (5–6 months of age) exposed to vehicle (white bars), 10 μM BAY 58-2667 (gray bars), or 10 μM BAY 58-2667 plus 10 μM ODQ (black bars). cGMP levels are expressed as mean ± SEM of 5–10 animals. *P < 0.05; **P < 0.01; ***P < 0.001.