title: 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.affiliation: Institute of Cardiovascular Research, Bayer HealthCare, Wuppertal, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schmidt
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Nedvetsky
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Nedvetskaya
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: H S
authors.forename: Sabine
authors.initials: S
authors.lastname: Meurer
authors.forename: Martin
authors.initials: M
authors.lastname: Deile
authors.forename: Ashraf
authors.initials: A
authors.lastname: Taye
authors.forename: Andreas
authors.initials: A
authors.lastname: Knorr
authors.forename: Harald
authors.initials: H
authors.lastname: Lapp
authors.forename: Helmut
authors.initials: H
authors.lastname: Müller
authors.forename: Yagmur
authors.initials: Y
authors.lastname: Turgay
authors.forename: Christiane
authors.initials: C
authors.lastname: Rothkegel
authors.forename: Adrian
authors.initials: A
authors.lastname: Tersteegen
authors.forename: Barbara
authors.initials: B
authors.lastname: Kemp-Harper
authors.forename: Werner
authors.initials: W
authors.lastname: Müller-Esterl
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000502:physiology*; D018929:Cell Culture Techniques; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006162:Guanylate Cyclase / Q000187:drug effects / Q000502:physiology*; D006418:Heme; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011651:Pulmonary Artery; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D013552:Swine; D014664:Vasodilation
chemical_list: D001565:Benzoates; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; C480588:BAY 58-2667; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP