Helmut Müller

Publications of Helmut Müller

• Heat shock protein 90 regulates stabilization rather than activation of soluble guanylate cyclase.

  Authors: Pavel I Nedvetsky, Sabine Meurer, Nils Opitz, Tatiana Y Nedvetskaya, Helmut Müller, Harald H H W Schmidt

  FEBS letters. 02/2008; 582(2):327-31.

  Endothelium-derived nitric oxide (NO) activates the heterodimeric heme protein soluble guanylate cyclase (sGC) to form cGMP. In different disease states, sGC levels and activity are diminishedEndothelium-derived nitric oxide (NO) activates the heterodimeric heme protein soluble guanylate cyclase (sGC) to form cGMP. In different disease states, sGC levels and activity are diminished possibly involving the sGC binding chaperone, heat shock protein 90 (hsp90). Here we show that prolonged hsp90 inhibition in different cell types reduces protein levels of both sGC subunits by about half, an effect that was prevented by the proteasome inhibitor MG132. Conversely, acute hsp90 inhibition affected neither basal nor NO-stimulated sGC activity. Thus, hsp90 is a molecular stabilizer for sGC tonically preventing proteasomal degradation rather than having a role in short-term activity regulation.

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

  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

  The Journal of clinical investigation. 10/2006; 116(9):2552-61.

  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 strongROS 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.

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• Effects of nitric oxide on sGC redox states

  Authors: Martin Deile, César Ibarra-Alvardo, Pavel Nedvetsky, Helmut Müller, Barbara Kemp-Harper, Johannes-Peter Stasch, HHHW Schmidt

  BMC Pharmacology. 01/2005;

• Formation of quasi-covalent sGC α₁/β₁-heterodimers by ODQ-induced oxidation of the prosthetic heme moiety

  Authors: Tatiana Nedvetskaya, Pavel Nedvetsky, Sanchaita Sonar, Helmut Müller, Albert Sickmann, Peter Schmidt, Petra Kronich, Johannes-Peter Stasch, Harald Schmidt

  BMC Pharmacology. 01/2005;

• Calcium-dependent membrane association sensitizes soluble guanylyl cyclase to nitric oxide.

  Authors: Ulrike Zabel, Christoph Kleinschnitz, Phil Oh, Pavel Nedvetsky, Albert Smolenski, Helmut Müller, Petra Kronich, Peter Kugler, Ulrich Walter, Jan E Schnitzer, Harald H H W Schmidt

  Nature cell biology. 05/2002; 4(4):307-11.

  Nitric oxide (NO) is a ubiquitous, cell-permeable intercellular messenger. The current concept assumes that NO diffuses freely through the plasma membrane into the cytoplasm of a target cell, whereNitric oxide (NO) is a ubiquitous, cell-permeable intercellular messenger. The current concept assumes that NO diffuses freely through the plasma membrane into the cytoplasm of a target cell, where it activates its cytosolic receptor enzyme, soluble guanylyl cyclase (sGC). Recent evidence, however, suggests that cellular membranes are not only the predominant site of calcium-dependent NO synthesis, but also the site of its distribution and binding. Here we extend this concept to NO signalling to show that active sGC is partially associated with the plasma membrane in a state of enhanced NO sensitivity. After cellular activation, sGC further translocates to the membrane fraction in human platelets and associates with the NO-synthase-containing caveolar fraction in rat lung endothelial cells, in a manner that is dependent on the concentration of intracellular calcium. Our data suggest that the entire NO signalling pathway is more spatially confined than previously assumed and that sGC dynamically translocates to the plasma membrane, where it is sensitized to NO.