Schoedon-Geiser
Fakultäten » Medizinische Fakultät » Klinik und Poliklinik für Innere Medizin » Prof. Dr. Andreas Schaffner (emeritiert) » Schoedon-Geiser
Completed research project
| Title / Titel | Nitric oxide synthases in the vascular system: Regulatory role of the tetrahydrobiopterin cofactor. | ||||||||
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| Abstract (PDF, 14 KB) | |||||||||
| Summary / Zusammenfassung | Nitric oxide (NO) emerged to play crucial roles as an inter-and intra-cellular signaling molecule. In 1989, tetrahydrobiopterin (BH4) has been recognized as obligatory cofacor of NO synthases, a family of 3 enzymes differing in structure, regulation and tissue distribution. Our research focusses on the regulatory role of BH4 on NO production in the vascular system.The molecular mechanisms of the functional link between BH4 and NO synthesis is investigated in vascular endothelial and smooth muscle cells.Thereby, the expression of the constitutive and inducible isoforms of NO synthase as well as the BH4 biosynthetic enzymes GTP cyclohydrolase (GTPCH) and 6-pyruvoyl-tetrahydropterin synthase (PTPS ) are studied under both inflammatory and normal conditions. Our studies recenly revealed that overproduction of vascular NO under inflammatory conditions is caused by overexpression of inducible NO synthase (iNOS) in smooth muscle cells due to post-transcriptional effects of BH4 on the iNOS mRNA stability. Furthermore, we could show that inflammatory stimuli trigger a strong increase of BH4 production in vascular endothelial cells by enhancing mRNA expression of both the BH4 synthetic enzymes GTPCH and PTPS. The mechanisms behind these molecular events are now investigated in detail. Our research not only contributes to the understanding of the physiologic and pathophysiologic regulation of the vascular tone by the NO/BH4 pathways operative in cells of the vascular system. It will also have direct clinical implications for treatment of pathological processes caused by too much or too less NO production, such as septic shock or allograft reperfusion injury. Weitere Informationen: The Tetrahydrobiopterin Home Page |
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| Publications / Publikationen | Reduction of lung allograft ischemia/reperfusion injury by tetrahydrobioipterin cofactor of NOS. Hillinger S, Schoedon G, Walter R, Zollinger A, Stammberger U, Speich R, Schaffner A, Weder W, Schmid, RA Transplantation Proceedings 1999 Feb-Mar; 31 (1-2): 183-4Regulation of 6-pyruvoyltetrahydropterin synthase activity and messenger RNA abundance in human vascular endothelial cells. Linscheid-P; Schaffner-A; Blau-N; Schoedon-G Circulation. 1998 Oct 27; 98(17): 1703-6 Induction of tetrahydrobiopterin synthesis in human umbilical vein smooth muscle cells by inflammatory stimuli. Walter-R; Linscheid-P; Blau-N; Kierat-L; Schaffner-A; Schoedon-G Immunol-Lett. 1998 Jan; 60(1): 13-7 Modulation of inducible nitric oxide synthase mRNA stability by tetrahydrobiopterin in vascular smooth muscle cells. Linscheid-P; Schaffner-A; Schoedon-G Biochem-Biophys-Res-Commun. 1998 Feb 4; 243(1): 137-41 Inhalation of the nitric oxide synthase cofactor tetrahydrobiopterin in healthy volunteers. Walter-R; Blau-N; Schaffner-A; Schneemann-M; Speich-R; Stocker-R; Naujeck-B; Schoedon-G Am-J-Respir-Crit-Care-Med. 1997 Dec; 156(6): 2006-10 Nitrite generation in interleukin-4-treated human macrophage cultures does not involve the nitric oxide synthase pathway. Schneemann-M; Schoedon-G; Linscheid-P; Walter-R; Blau-N; Schaffner-A J-Infect-Dis. 1997 Jan; 175(1): 130-5 Tetrahydrobiopterin synthesis precedes nitric oxide-dependent inhibition of insulin secretion in INS-1 rat pancreatic beta-cells. Laffranchi-R; Schoedon-G; Blau-N; Spinas-GA Biochem-Biophys-Res-Commun. 1997 Apr 7; 233(1): 66-70 Crucial role of interferon consensus sequence binding protein, but neither of interferon regulatory factor 1 nor of nitric oxide synthesis for protection against murine listeriosis. Fehr-T; Schoedon-G; Odermatt-B; Holtschke-T; Schneemann-M; Bachmann-MF; Mak-TW; Horak-I; Zinkernagel-RM J-Exp-Med. 1997 Mar 3; 185(5): 921-31 Effects of activating and deactivating cytokines on the functionally linked tetrahydrobiopterin. No pathways in vascular smooth muscle cells. Walter-R; Blau-N; Kierat-L; Schaffner-A; Schoedon-G Immunol-Lett. 1996 Dec 1; 54(1): 25-9 Nitric oxide and infection: another view. Schoedon-G; Schneemann-M; Walter-R; Blau-N; Hofer-S; Schaffner-A Clin-Infect-Dis. 1995 Oct; 21 Suppl 2: S152-7 Nitric oxide production depends on preceding tetrahydrobiopterin synthesis by endothelial cells: selective suppression of induced nitric oxide production by sepiapterin reductase inhibitors. Schoedon-G; Blau-N; Schneemann-M; Flury-G; Schaffner-A Biochem-Biophys-Res-Commun. 1994 Mar 15; 199(2): 504-10 Tetrahydrobiopterin as another EDRF in man. Schaffner-A; Blau-N; Schneemann-M; Steurer-J; Edgell-CJ; Schoedon-G Biochem-Biophys-Res-Commun. 1994 Nov 30; 205(1): 516-23 Tetrahydrobiopterin is a secretory product of murine vascular endothelial cells. Walter-R; Schaffner-A; Blau-N; Kierat-L; Schoedon-G Biochem-Biophys-Res-Commun. 1994 Sep 30; 203(3): 1522-6 Differential regulation of constitutive and inducible nitric oxide production by inflammatory stimuli in murine endothelial cells. Walter-R; Schaffner-A; Schoedon-G Biochem-Biophys-Res-Commun. 1994 Jul 15; 202(1): 450-5 Immunovascular communication: activation and deactivation of murine endothelial cell nitric oxide synthase by cytokines. Schneemann-M; Schoedon-G; Frei-K; Schaffner-A Immunol-Lett. 1993 Feb; 35(2): 159-62 Modulation of human endothelial cell tetrahydrobiopterin synthesis by activating and deactivating cytokines: new perspectives on endothelium-derived relaxing factor. Schoedon-G; Schneemann-M; Blau-N; Edgell-CJ; Schaffner-A Biochem-Biophys-Res-Commun. 1993 Nov 15; 196(3): 1343-8 |
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| Keywords / Suchbegriffe | endothelial cells, smooth muscle cells, nitric oxide, tetrahydrobiopterin, cofactor, vascular system, inflammation, pathophysiology. | ||||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung) |
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| Duration of Project / Projektdauer | to May 2002 |