A novel role for thiols in the regulation of platelet function
Reddy, Emily C. (2013) A novel role for thiols in the regulation of platelet function. PhD thesis, Dublin City University.
Full text available as:
Platelets are small, megakaryocyte-derived cell fragments that play a key role in haemostasis. Platelet receptors, in particular integrins, contain high numbers of reactive cysteines making them prime targets for thiol modifications. The plasma redox environment is controlled by low-molecular-weight thiol couples along with reactive oxygen/nitrogen species (RONS) and their respective scavengers. ‘Stress’ arises when an imbalance occurs within this tightly regulated redox system. The aim of this thesis is to investigate the role of thiol signalling in platelet function and examine the modulation of this signalling by the external redox environment. Previous work in our laboratory has demonstrated thiol/disulphide exchange to be critical to integrin IIb3 function.
In this study, a significant increase in purified integrin IIb3 free thiols was observed upon activation. Integrin activation was inhibited in a reducing redox environment. Subsequently, it was found that platelet surface thiol population was increased upon stimulation with collagen only. Platelet activation by collagen was exclusively inhibited by a reducing external redox environment, with a concomitant modulation of the platelet surface thiol population. These results pointed to an exquisitely redox sensitive element of the collagen activation pathway, namely integrin 21. Furthermore, the phosphorylation state of VASP (vasodilator-stimulated phosphoprotein), a protein found downstream of integrin 21, was found to be affected by an external reducing redox environment in collagen stimulated platelets only. These results indicate modification of the receptor by the external environment can also impact on downstream, intra-platelet signalling events. These findings suggest a potential
novel therapeutic target for diseases with a characteristic imbalanced redox environment in which thromboembolic events are common, such an inflammatory bowel disease.
Archive Staff Only: edit this record