ZINC IONS POTENTIATE ADENOSINE DIPHOSPHATE-INDUCED PLATELET-AGGREGATION BY ACTIVATION OF PROTEIN-KINASE-C

Zinc deficiency has been linked to a bleeding tendency and impaired wo und healing in several disease states. A number of investigators have suggested that zinc ions play a role in platelet aggregation in vitro as well as in in vivo studies. The purpose of the present study was to explore the mechanism by which adenosine diphosphate (ADP) and Zn2+ m ay act cooperatively during activation of blood platelets. We demonstr ate that Zn2+ alone does not affect either formation of thromboxane A( 2) or intracellular calcium mobilization in platelets. On the other ha nd, we show that ADP and Zn2+ exert a cooperative effect on the phosph orylation of P-47 protein (pleckstrin), a substrate of protein kinase C in platelets. The inhibitory effect of this reaction by the compound Ro31, a specific inhibitor of the regulatory domain of protein kinase C, was compatible with our contention that Zn2+ may act directly on p rotein kinase C. Our study provides evidence that zinc ions present in plasma or platelets may modulate ADP-induced platelet aggregation. N, N,N',N'-tetrakis(2-pyridylmethyl)ethyl enediamine (TPEN), a zinc chela tor, blocked ADP-induced platelet aggregation. This aggregation was re stored by 10 mu mol/L of Zn2+ but not by other ions. Also, a Zn2+ iono phore, pyrithione, potentiated the ADP-induced platelet aggregation an d this potentiation was blocked by TPEN. Experiments with the zinc ion ophore suggest that intracellular zinc ions play an important role in activation of platelets, and in the absence of other platelet agonists it appears that it may be a requirement for ADP-induced platelet aggr egation to occur.