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

Content Provider	PubMed Central
Author	Stasch, Johannes-peter Schmidt, Peter M. Nedvetsky, Pavel I. Nedvetskaya, Tatiana Y. Kumar, H. S. Arun Meurer, Sabine Martin, Deile Taye, Ashraf Knorr, Andreas Lapp, Harald Müller, Helmut Yagmur, Turgay Christiane, Rothkegel Tersteegen, Adrian Barbara, Kemp-harper Werner, Müller-esterl Schmidt, Harald H. H. W.
Copyright Year	2006
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.
Related Links	http://dx.doi.org/10.1172/jci28371
Ending Page	2561
Page Count	10
Starting Page	2552
File Format	PDF
ISSN	00219738
Journal	Journal of Clinical Investigation
Issue Number	9
Volume Number	116
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2006-09-01
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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