Refine
Document Type
- Article (2) (remove)
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- fibrinolysis (2) (remove)
Institute
- Medizin (2) (remove)
Diabetes mellitus is the fifth most common cause of death worldwide. Due to its chronic nature, diabetes is a debilitating disease for the patient and a relevant cost for the national health system. Type 2 diabetes mellitus is the most common form of diabetes mellitus (90% of cases) and is characteristically multifactorial, with both genetic and environmental causes. Diabetes patients display a significant increase in the risk of developing cardiovascular disease compared to the rest of the population. This is associated with increased blood clotting, which results in circulatory complications and vascular damage. Platelets are circulating cells within the vascular system that contribute to hemostasis. Their increased tendency to activate and form thrombi has been observed in diabetes mellitus patients (i.e., platelet hyperactivity). The oxidative damage of platelets and the function of pro-oxidant enzymes such as the NADPH oxidases appear central to diabetes-dependent platelet hyperactivity. In addition to platelet hyperactivity, endothelial cell damage and alterations of the coagulation response also participate in the vascular damage associated with diabetes. Here, we present an updated interpretation of the molecular mechanisms underlying vascular damage in diabetes, including current therapeutic options for its control.
The emerging relapsing fever spirochete Borrelia (B.) miyamotoi is transmitted by ixodid ticks and causes the so-called hard tick-borne relapsing fever or B. miyamotoi disease (BMD). More recently, we identified a surface-exposed molecule, CbiA exhibiting complement binding and inhibitory capacity and rendering spirochetes resistant to complement-mediated lysis. To gain deeper insight into the molecular principles of B. miyamotoi-host interaction, we examined CbiA as a plasmin(ogen) receptor that enables B. miyamotoi to interact with the serine protease plasmin(ogen). Recombinant CbiA was able to bind plasminogen in a dose-dependent fashion. Moreover, lysine residues appear to play a crucial role in the protein-protein interaction as binding of plasminogen was inhibited by the lysine analog tranexamic acid as well as increasing ionic strength. Of relevance, plasminogen bound to CbiA can be converted by urokinase-type plasminogen activator (uPa) to active plasmin which cleaved both, the chromogenic substrate S-2251 and its physiologic substrate fibrinogen. Concerning the involvement of specific amino acids in the interaction with plasminogen, lysine residues located at the C-terminus are frequently involved in the binding as reported for various other plasminogen-interacting proteins of Lyme disease spirochetes. Lysine residues located within the C-terminal domain were substituted with alanine to generate single, double, triple, and quadruple point mutants. However, binding of plasminogen to the mutated CbiA proteins was not affected, suggesting that lysine residues distant from the C-terminus might be involved in the interaction.