Research Area E: Redox regulation: ischemia, hypoxia, and reactive oxygen species
| Research Area Leaders | |
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Institute for Cardiovascular Physiology Vascular Research Center Goethe University Frankfurt Theodor-Stern-Kai 7 60590 Frankfurt/Main |
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ECCPS Justus-Liebig University Giessen Aulweg 130 35392 Giessen |
| Faculty involved | |||
|---|---|---|---|
| T. Acker | S. Bellusci | R.P. Brandes | T. Braun |
| B. Brüne | S. Dimmeler | W. Eberhardt | J. Eble |
| I. Fleming | G.Geisslinger | H.A. Ghofrani | W. Kummer |
| R.E. Morty | J. Pfeilschifter | M. Potente | S. Rohrbach |
| H. Sauer | K.D. Schlüter | R. Schulz | R.T. Schermuly |
| L. Schmitz | D. Steinhilber | N. Weissmann | H. v. Melchner |
| R. Voswinckel | K. Zacharowski | A.M. Zeiher | |
Summary
Alterations in cellular oxygen supply are key events in most cardio-pulmonary diseases. Ischemia, hypoxia and reoxygenation are all directly linked to changes in the cellular redox state and the generation of reactive oxygen species (ROS). Hypoxia, ROS and in a broader sense gaseous transmitters that alter the redox environment (H2S, CO, NO) also play an important role as signalling molecules, and specialised enzymes have been identified as sources of these redox mediators. In this area, the molecular mechanisms underlying redox-signalling will be identified, focussing on specific redox-mediated protein and lipid modifications to uncover novel targets that specifically interfere with cardio-pulmonary disease processes. The aim of this area is to shift the clinical approach away from symptomatic treatment with antioxidants towards a specific site directed inhibitory strategy, by utilising compounds that target individual generator and effector systems of redox-signalling. The concept of specific and compartmentalised redox-signalling will be tested in samples obtained from patients, animal and organ experiments as well as tissue culture. Site-specific probes to alter and analyse redox-signalling will be developed.
Most relevant publications of the Research Area E
1. Köhler D, Straub A, Weissmüller T, Faigle M, Bender S, Lehmann R, Wendel HP, Kurz J, Walter U, Zarachowski K, Rosenberger P. Phosphorylation of vasodilator-stimulated phosphoprotein prevents platelet-neutrophil complex formation and dampens myocardial ischemia-reperfusion injury. Circulation 123:2579-90, 2011
2. Krasteva G, Canning BJ, Hartmann P, Veres TZ, Papadakis T, Mühlfeld C, Schliecker K, Tallini YN, Braun A, Hackstein H, Baal N, Weihe E, Schütz B, Kotlikoff MI, Ibanez-Tallon I, Kummer W. Cholinergic chemosensory cells in the trachea regulate breathing. Proc Natl Acad Sci USA 108:9478-83, 2011
3. Niemann B, Chen Y, Teschner, M, Li L, Silber RE, Rohrbach S. Obesity induces signs of premature cardiac aging in younger patients: Role of mitochondria. J Am Coll Cardiol 57:577-85, 2011
4. Pullamsetti SS, Savai R, Schaefer MB, Wilhelm J, Ghofrani HA, Weissmann N, Schudt C, Fleming I, Mayer K, Leiper J, Seeger W, Grimminger F, Schermuly RT. cAMP phosphodiesterase inhibitors increases nitric oxide production by modulating dimethylarginine dimethylaminohydrolases. Circulation 123:1194-204, 2011
5. Sachs UJ, Wasel W, Bayat B, Bohle RM, Hattar K, Berghöfer H, Reil A, Bux J, Bein G, Santoso S, Weissmann N. Mechanism of transfusion-related acute lung injuryinduced by HLA class II antibodies. Blood 117:669-77, 2011
6. Schmidt MV, Paulus P, Kuhn AM, Weigert A, Morbitzer V, Zarachowski K, Kempf VA, Brüne B, von Knethen A. PPARgamma-Induced T-Cell Apoptosis Reduces Survival During Polymicrobial Sepsis. Am J Respir Crit Care Med 184:64-74, 2011
7. Tegeder I, Scheving R, Wittig I, Geisslinger G. SNO-ing at the nociceptive synapse? Pharmacol Rev 62: 366-389, 2011
8. Ten Freyhaus H, Dagnell M, Leuchs M, Vantler M, Berghausen E, Caglayan E, Weissmann N, Dahal BK, Schermuly RT, Ostman A, Kappert K, Rosenkranz S. Hypoxia Enhances PDGF Signaling in the Pulmonary Vasculature by Downregulation of Protein Tyrosine Phosphatases. Am J Respir Crit Care Med 183:1092-1102, 2011
9. Schröder K, Schütz S, Schlöffel I, Bätz S, Takac I, Weissmann N, Michaelis UR, Koyanagi M, Brandes RP. Hepatocyte growth factor induces a pro-angiogenic phenotype and mobilizes endothelial progenitor cells by activating Nox2. Antioxid Redox Signal 15:915-23, 2011
10. Menrad H, Werno C, Schmid T, Copanaki E, Deller T, Brüne B. Roles of hypoxia-inducible factor-1α versus HIF-2α in the survival of hepatocellular tumor spheroids. Hepatology. 51:2183-92, 2010
11. Renner F, Moreno R, Schmitz ML. SUMOylation-dependent localization of IKKα in PML nuclear bodies is essential for protection against DNA damage-triggered cell death. Mol Cell 37:503-15, 2010
12. Zhang M, Brewer AC, Schröder K, Santos CXC, Grieve DJ, Wang M, Anilkumar N, Yu B, Dong X, Walker SJ, Brandes RP, Shah AM: NADPH oxidase-4 mediates protection againstchronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci USA 107:18121-26, 2010
13. Calzado MA, de la Vega L, Möller A, Bowtell DL, Schmitz ML. An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol 11:85-91, 2009
14. Herr B, Zhou J, Werno C, Menrad H, Namgaladze D, Weigert A, Dehne N, Brüne B. The supernatant of apoptotic cells causes transcriptional activation of hypoxia-inducible factor-1a in macrophages via sphingosine-1-phosphate and transforming growth factor-ß. Blood 114:2140-48, 2009
15. Loot AE, Schreiber JG, Fisslthaler B, Fleming I. Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase. J Exp Med 206:2889-96, 2009
16. Renner F, Schmitz ML. Autoregulatory feedback loops terminating the NF-κB response. Trends Biochem Sci 34:128-35, 2009
17. Roth M, Rupp M, Hofmann S, Mittal M, Fuchs B, Sommer N, Parajuli N, Quanz K, Schubert D, Dony E, Schermuly RT, Ghofrani HA, Sausbier U, Rutschmann K, Wilhelm S, Seeger W, Ruth P, Grimminger F, Sausbier M, Weissmann N. Heme oxygenase-2 and large conductance Ca2+-activated K+ channels: lung vascular effects of hypoxia. Am J Respir Crit Care Med 180:353-64, 2009
18. Schröder K, Kohnen A, Aicher A, Liehn EA, Büchse T, Stein S, Weber C, Dimmeler S, Brandes RP. NADPH oxidase Nox2 is required for hypoxia-induced mobilization of endothelial progenitor cells. Circ Res 105:537-44, 2009
19. Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle RM, Seeger W, Weaver TE, Guenther A. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 178:838-46, 2008
20. Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet 371:475-82, 2008
21. Kwapiszewska G, Wygrecka M, Marsh LM, Schmitt S, Trösser R, Wilhelm J, Helmus K, Eul B, Zakrzewicz A, Ghofrani HA, Schermuly RT, Bohle RM, Grimminger F, Seeger W, Eickelberg O, Fink L, Weissmann N. Fhl-1, a new key protein in pulmonary hypertension. Circulation 118:1183-94, 2008
22. Randriamboavonjy V, Pistrosch F, Bolck B, Schwinger RHG, Dixit M, Badenhoop K, Cohen RA, Busse R, Fleming I. Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATPase and μ-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone. Circulation 117:52-60, 2008
23. Mittal M, Roth M, König P, Hofmann S, Dony E, Goyal P, Selbitz AC, Schermuly RT, Ghofrani HA, Kwapiszewska G, Kummer W, Klepetko W, Hoda MA, Fink L, Hänze J, Seeger W, Grimminger F, Schmidt HH, Weissmann N. Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 101:258-67, 2007
24. Dimmeler S, Zeiher AM. A "reductionist" view of cardiomyopathy. Cell 130:401-2, 2007
25. Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N, Ghofrani HA, Kaulen C, Dunkern T, Schudt C, Voswinckel R, Zhou J, Samidurai A, Klepetko W, Paddenberg R, Kummer W, Seeger W, Grimminger F. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension - target for reverse remodeling therapy. Circulation 115:2331-39, 2007
26. Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch JP, Gnoth MJ, Seeger W, Grimminger F, Schermuly RT. Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation 113: 286-95, 2006
27. Grebe M, Eisele HJ, Weissmann N, Schaefer C, Tillmanns H, Seeger W, Schulz R. Antioxidant Vitamin C Improves Endothelial Function in Obstructive Sleep Apnea. Am. J. Respir Crit Care Med 15:897-901, 2006
28. Roscic A, Möller A, Calzado MA, Renner F, Wimmer VC, Gresko E, Schmid Lüdi K, Schmitz ML. Phosphorylation dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2. Mol Cell 24:77-89, 2006
29. Sasaki K, Heeschen C, Aicher A, Ziebart T, Jonold J, Urbich C, Rössig L, Koehl U, Koyanagi M, Mohamed A, Brandes RP, Martin H, Zeiher AM, Dimmeler S. Ex vivo pre-treatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy. Proc Natl Acad Sci USA 103:14537-41, 2006
30. Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, Olschewski A, Storch U, Mederos y Schnitzler M, Ghofrani HA, Schermuly RT, Pinkenburg O, Seeger W, Grimminger F, Gudermann T. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci USA 103:19093-8, 2006