Sabetkar, Mojhgan; (2004) The mechanism of the synergism between NO and H2O2 on the inhibition of platelets aggregation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Nitric oxide (NO) is a potent inhibitor of platelets activation and its mechanism of action is to increase intracellular cyclic GMP level. A strong synergism has been shown to exist between low concentrations of hydrogen peroxide (H2O2) and nitric oxide in the inhibition of agonist-induced platelet aggregation. The aim of this thesis was to establish the mechanism of this interaction. It was established that hydrogen peroxide in the presence of NO had no additional effect on the activity of pure soluble guanylyl cyclase or its activity in platelet lysates and cytosol. However, H2O2 was found to increase the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) a target for cGMP and cAMP. This occurs both in the presence and in absence of low concentrations of NO and at submicromolar concentrations of the peroxide. These actions of H2O2 were inhibited largely by an inhibitor of cyclic AMP-dependent protein kinase, even though H2O2 did not increase cyclic AMP. This inhibitor reversed the inhibition of platelets induced by combinations of NO and H2O2 at low concentrations. The results suggest that the action on VASP may be one site of action of H2O2, but that this event alone may not lead to inhibition of platelets. Another modification of the proteins related to NO is the nitration of aromatic amino acids, particularly tyrosines through the formation of the reactive nitrogen species, peroxynitrite. I have now shown that H2O2 also increases the nitration of VASP and other platelet proteins and that the nitration is inhibited by the anti-oxidant epigallocatechin gallate. In addition to this founding, nitrated proteins were also found in the basal (non-stimulated) platelets immediately after separation of platelets from plasma.

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