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Bedeutung der Leptinrezeptor-vermittelten Aktivierung des Transkriptionsfaktors STAT3 für die Effekte des Adipokins Leptin auf Blutplättchen

dc.contributor.advisorSchäfer, Katrin Prof. Dr.
dc.contributor.authorStroebe, Kristina Friederike
dc.titleBedeutung der Leptinrezeptor-vermittelten Aktivierung des Transkriptionsfaktors STAT3 für die Effekte des Adipokins Leptin auf Blutplättchende
dc.title.translatedRelevance of leptin receptor-induced activation of the transcriptional factor STAT3 for the effects of the adipokine leptin on plateletsde
dc.contributor.refereeSchäfer, Katrin Prof. Dr.
dc.description.abstractengOther studies have shown that the leptin receptor is also expressed on platelets (Nakata et al. 1999) and that leptin dose-dependent promotes platelet aggregation. According to these findings there have been many investigations of leptin and its influence to platelets. It was found out that leptin promotes both arterial (z.B. Konstantinides et al. 2001a, Bodary et al. 2002) and venous thrombosis (Konstantinides et al. 2004). Even the way of intracellular signal transduction, which is responsible for the prothrombotic effects of leptin, is almost decoded. The central signalling molecule is Jak2. Phosphorylation of leptin receptor`s different tyrosine residues and other signal transduction proteins leads to thromboxane generation and increases activation of fibrinogen receptor (Dellas et al. 2007). Furthermore the transcription factor STAT3 is phosphorylated by Jak2. At least it remained to be answered whether STAT3 has an effect to activation respectively adhesion of blood platelets. That was the aim of this study. At the beginning there have been investigations of hematopoiesis and platelet function to exclude basic differences between wild type mice and mice, which are based on a point mutation in tyrosine residue 1138 of the leptin receptor, unable to do a leptin-induced STAT3-activation. Because there were no significant differences regarding to blood count or bleeding time we had the same requirements for the following experiments. As a part of the aggregation cascade platelet adhesion was investigated next. In summary it could be shown that adhesion is fibrinogen-specific and leptin (strongest effect with 10 ng/ml) in both genotypes led to an increase of adhesion to immobilized fibrinogen. Furthermore unstimulated platelets of ObRs/s-mice were less adherend in comparison to wild type platelets. A leptin-induced increase in platelet surface area could be demonstrated in both populations, but only significant in ObRs/s mice. To pursue the aggregation cascade, experiments concerning the expression of αIIbβ3 , binding of soluble fibrinogen an platelet activation followed. Using flow cytometry analysis the direct (using a specific fibrinogen receptor antibody) and indirect (about an increase of fibrinogen binding) activation of fibrinogen receptor were detectable. These results assumed that leptin induces an increase of fibrinogen receptor activation. But this activation only appeared after stimulation with ADP. Leptin alone or leptin combined with ADP had no (additional) effect. This result did not really surprise because it was already known 67 that leptin is just a weak agonist which even showed in human platelets only little effects (Dellas et al. 2007). The P-selectin-expression, which goes along with platelet activation, should be demonstrated by using a specific antibody (CD62P). Once again leptin alone had no effect. Only the very strong agonist pma generated an increase of platelet activation. Just observing these results leptin has no influence on platelet activation in mice. Based on the results of adhesion experiments there are two possible explanations for the lack of leptin effect on platelet activation. For instance leptin`s agonistic effect could be too weak for this experiment or mice platelets could have a higher threshold of activation than human platelets. Because there were no essential differences concerning hematopoiesis, platelet adhesion and expression of fibrinogen receptor between both genotypes, the aggregation experiments were cancelled. The expected results (no differences) would be out of all proportion to the amount of blood we needed for these experiments. So far STAT3 did not seem to be important for the investigated process but at least examination of signal transduction was left. At the beginning the expected Jak2 activation could be detected by using western blot analysis. The investigation of the next activation step surprisingly showed that even in ObRs/s mice there is STAT3 activation, which was in comparison to the wildtype mice less distinctive and shorter. To exclude a method specific result, the flow cytometry was chosen as another method. The leptin-induced STAT3 activation could be reproduced. This detection led to the assumption that leptin-induced STAT3 activation runs out an alternative, tyrosine 1138-independent way, as well. In conclusion, the results of this study declare that the leptin receptor-induced STAT3 activation does not have any consequences of leptin`s effects regarding the amount and function of murine platelets and does not play an outstanding role for platelet activation and adhesion. So leptin-induced STAT3 activation does not seem to be another risk factor for thrombosis
dc.contributor.coRefereeMeyer, Thomas Prof. Dr.
dc.affiliation.instituteMedizinische Fakultätde
dc.subject.gokfullMedizin (PPN619874732)de

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