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 wound 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+ may act cooperatively during activation of blood platelets. We demonstrate that Zn2+ alone does not affect either formation of thromboxane A2 or intracellular calcium mobilization in platelets. On the other hand, we show that ADP and Zn2+ exert a cooperative effect on the phosphorylation 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 protein 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)ethylenediamine (TPEN), a zinc chelator, blocked ADP-induced platelet aggregation. This aggregation was restored by 10 mumol/L of Zn2+ but not by other ions. Also, a Zn2+ ionophore, pyrithione, potentiated the ADP-induced platelet aggregation and this potentiation was blocked by TPEN. Experiments with the zinc ionophore 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 aggregation to occur.
Kowalska
M A
MA
Department of Physiology, Temple University, Philadelphia, PA 19140.
Juliano
D
D
Trybulec
M
M
Lu
W
W
Niewiarowski
S
S
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D001798:Blood Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D005029:Ethylenediamines / Q000494:pharmacology; D006801:Humans; D007477:Ions; D010750:Phosphoproteins; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects*; D011493:Protein Kinase C / Q000378:metabolism*; D047428:Protein Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D013871:Thiones; D013928:Thromboxane A2 / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
D001798:Blood Proteins; D002614:Chelating Agents; D005029:Ethylenediamines; D007477:Ions; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013871:Thiones; C039077:platelet protein P47; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; C008704:pyrithione; D011493:Protein Kinase C; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D002118:Calcium