Role of Vasodilator Stimulated Phosphoprotein (VASP) during Hypoxia, Inflammation and Ischemia-Reperfusion Injury.
Zusammenfassung der Projektergebnisse
Hypoxia and acute inflammation are associated with a disruption of cellular barriers. Vasodilator phosphostimulated protein (VASP) is a crucial cytoplasmatic actin binding protein controlling paracellular permeability as well as activation of thrombocytes. Changes of VASP expression can have significant impact on barrier function, on thrombocyte activation and as such the intergrity of organ function. In the current grant proposal we have pursued the role of VASP during several important clinical conditions. We found that VASP is repressed through inflammatory cytokines in-vitro and this repression significantly affects barrier function of the affected cells. This finding was translated into in-vivo evidence in two models of lung injury. Here we found that the non-hematopoetic VASP repression is associated with a significant reduction in pulmonary barrier properties, increased infiltration of leukocytes into the alveolar space and decreased functional outcome. When turning our attention to the role of VASP for thrombocyte function, we found that VASP phosphorylation is of significant importance for the formation of platelet-neutrophil complexes and the translocation of these PNCs into inflammatory tissue sites. During myocardial ischemia-reperfusion (IR) injury in-vivo we found that VASP depletion was associated with significant cardioprotective potential. During experiments in chimeric animals we found that this is confined to hematopoietic VASP depletion. The observed cardioprotective potential was mediated through the reduced formation of PNCs within the ischemic tissues. Furthermore, we were able to demonstrate the protective potential of VASP phosphorylation during myocardial IR injury. VASP phosphorylation on Ser153 and Ser235 through the use of Prostaglandin E1 or antrial natriuretic peptide resulted in reduced myocardial IR injury. This evidence was translated into a setting of hepatic IR injury, where we found that VASP depletion or phosphorylation reduced hepatic IR injury. In a final part of this grant proposal we described the protective potential of VASP for the endothelial barrier function during hypoxia, where it controls fluid exchange from the vascular to the extracellular space. In summary, the work in this grant proposal helped to make significant progress in the understanding of the role of VASP on organ function during inflammation and ischemia-reperfusion.
Projektbezogene Publikationen (Auswahl)
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Crucial role of platelet derived Vasodilator-Stimulated Phosphoprotein (VASP) during myocardial ischemia-reperfusion injury. Hamburg, Germany, 9. Kongress der Deutschen Interdisziplinären Vereinigung für Intensivmedizin und Notfallmedizin (DIVI), November, 2008. Intensivmedizin, Band 45, Supplement 1, I/22, FPV05/12
Köhler D., M. Schmit, S. Laucher, M. Faigle, T. Eldh, R. Lehmann, S.P. Colgan and P. Rosenberger
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2009 Nitric oxide metabolites, platelet activation, and myocardial ischemia reperfusion injury. Anesthesiology. 110(5):1198-1199
Köhler D, Mutz C, Mirakaj V, Rosenberger P
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Bedeutung von Vasodilatorstimulated Phosphoprotein im hepatischen Ischämie- und Reperfusionsschaden. Berlin, Deutschland, 11. Hauptstadtkongress der DGAI für Anästhesiologie und Intensivmedizin 2009, September 17-19, 2009. Book of Abstracts, Supplement Nr. 4 S628
Birk P., D. Köhler, S. Laucher und P. Rosenberger
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Crucial role of Vasodilator-Stimulated Phosphoprotein (VASP) during myocardial ischemia-reperfusion injury. Leipzig, Germany, 56. Jahrestagung der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin, Deutscher Anästhesie Congress (DAC), Mai, 2009. Kongressführer 2009, S. 75, 103.5
Köhler D., M. Schmit, S. Laucher, M. Faigle, R. Lehmann and P. Rosenberger
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Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolarcapillary barrier function during acute lung injury. FASEB J. 2009 Dec;23(12):4244-55
Henes J, Schmit MA, Morote-Garcia JC, Mirakaj V, Köhler D, Glover L, Eldh T, Walter U, Karhausen J, Colgan SP, Rosenberger P
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Vasodilator-Stimulated Phosphoprotein (VASP) beeinflusst den myokardialen Ischämie- und Reperfusionsschaden. Berlin, Deutschland, 11. Hauptstadtkongress der DGAI für Anästhesiologie und Intensivmedizin 2009, September 17-19, 2009. Book of Abstracts, Supplement Nr. 4 S648
Köhler D., S. Laucher, P. Birk, M. Faigle, R. Lehmann and P. Rosenberger
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Crucial role of vasodilator-stimulated phosphoprotein (VASP) during hepatic ischemiareperfusion injury. Munich, Germany, 8th Word Congress on Trauma, Shock, Inflammation and Sepsis, March 9-13, 2010. Book of Abstracts, Inflammation Research, Supplement 1, Vol.59, Session A111, (S. 50)
Köhler D., P. Birk, S. Laucher, V. Mirakaj and P. Rosenberger
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Netrin-1 dampens pulmonary inflammation during acute lung injury. Am J Respir Crit Care Med. 2010 Apr 15;181(8):815- 24
Mirakaj V, Thix CA, Laucher S, Mielke C, Morote-Garcia JC, Schmit MA, Henes J, Unertl KE, Köhler D, Rosenberger P
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Phosphorylation of vasodilator-stimulated phosphoprotein (VASP) influences transendothelial movement of platelets and affects myocardial ischemiareperfusion injury. Munich, Germany, 8th Word Congress on Trauma, Shock, Inflammation and Sepsis, March 9-13, 2010. Book of Abstracts, Inflammation Research, Supplement 1, Vol.59, Session A2, (S. 9)
Köhler D., M. Faigle, S. Zug, R. Lehmann, S.P. Colgan and P. Rosenberger
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The neuronal guidance protein netrin-1 reduces alveolar inflammation in a porcine model of acute lung injury. Crit Care. 2010;14(5):R189
Mutz C, Mirakaj V, Vagts DA, Westermann P, Waibler K, König K, Iber T, Nöldge- Schomburg G, Rosenberger P
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Vasodilator-Stimulated Phosphoprotein (VASP) beeinflusst den hepatischen Ischämie und Reperfusionsschaden. Nürnberg, Germany, 57. Jahrestagung der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin, Deutscher Anästhesie Congress (DAC), 19-22. Juni, 2010
Köhler D., P. Birk, S. Laucher and P. Rosenberger
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Phosphorylation of vasodilator-stimulated phosphoprotein (VASP) dampens hepatic ischemia-reperfusion injury. PLoS One. 2011;6(12):e29494
Köhler D, Birk P, König K, Straub A, Eldh T, Morote-Garcia JC, Rosenberger P
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Phosphorylation of vasodilatorstimulated phosphoprotein prevents platelet-neutrophil complexformation and dampens myocardial ischemia-reperfusion injury. Circulation. 2011 Jun 7;123(22):2579-90
Köhler D, Straub A, Weissmüller T, Faigle M, Bender S, Lehmann R, Wendel HP, Kurz J, Walter U, Zacharowski K, Rosenberger P
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Phosphorylation of vasodilator-stimulated phosphoprotein prevents platelet-neutrophil complex formation and dampens myocardial ischemia-reperfusion injury. Symposium Intensivmedizin und Intensivpflege Bremen, Februar 22-24, 2012
Köhler, D., A. Straub, T. Weissmüller, M. Faigle, S. Bender, R. Lehmann, HP. Wendel, J. Kurz, U. Walter, K. Zacharowski and P. Rosenberger
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Vasodilator phosphostimulated protein (VASP) protects endothelial barrier function during hypoxia. Inflammation. 2012 Apr;35(2):566-73
Schmit MA, Mirakaj V, Stangassinger M, König K, Köhler D, Rosenberger P
