Kurzfassung

NO, generated in both, endothelial cells and platelets, by the endothelial NO synthase (eNOS), reduces the activation, adhesion and aggregation of platelets. Furthermore, the recruitment of additional platelets to an established thrombus is constrained by NO. An absence of bioactive NO is associated with arterial thrombosis in animal models as well as in human individuals suffering from endothelial dysfunction.
Our aim is to elucidate if the endogenous eNOS inhibitor asymmetric...NO, generated in both, endothelial cells and platelets, by the endothelial NO synthase (eNOS), reduces the activation, adhesion and aggregation of platelets. Furthermore, the recruitment of additional platelets to an established thrombus is constrained by NO. An absence of bioactive NO is associated with arterial thrombosis in animal models as well as in human individuals suffering from endothelial dysfunction.
Our aim is to elucidate if the endogenous eNOS inhibitor asymmetric dimethylarginine (ADMA) accumulates as a result of reduced export and/or metabolism in endothelial cells and platelets. This hypothesis is based on the observation of an uncoupled eNOS (revealed through the production of superoxide radicals instead of NO) associated with a strongly reduced ADMA export in platelets from a patient. In addition, previous results show a considerable ADMA accumulation in endothelial cells under conditions not allowing ADMA efflux. We thus plan to investigate if ADMA accumulates in platelets under pro-atherothrombotic conditions and if this leads to uncoupling of eNOS. This approach will set the stage for further investigations of reduced ADMA export, platelet function and thrombus formation under experimental conditions. In a translational approach we will evaluate if we observe a reduced ADMA export in a larger number of patients and if this correlates with thrombotic events.
The focus of this project is on the role of transmembrane transport in the pathogenesis of thrombosis and hemostasis. Our objective is to identify ADMA export proteins and to resolve their function and regulation in thrombosis and hemostasis.» weiterlesen» einklappen