Jm. Xia et Bl. Odell, ZINC-DEFICIENCY IN RATS DECREASES THROMBIN-STIMULATED PLATELET-AGGREGATION BY LOWERING PROTEIN-KINASE-C ACTIVITY SECONDARY TO IMPAIRED CALCIUM-UPTAKE, Journal of nutritional biochemistry, 6(12), 1995, pp. 661-666
Aggregation of rat platelets, when stimulated by adenosine diphosphate
(ADP) or fluoride, is impaired by zinc deficiency, and the defect is
associated with a decreased uptake of external Ca2+. Zinc deficiency a
lso impairs the aggregatory response of platelets to phorbol myristate
acetate (PMA), an activator of protein kinase C, but low zinc status
decreases the PMA response only when calcium is added to the external
medium. The purpose of this study was to determine the role of protein
kinase C in rat platelet function and its relationship to the zinc de
ficiency pathology observed in platelets stimulated by thrombin (THR).
The percent of maximal aggregation and the concentration of cytosolic
-free Ca2+ were measured in washed platelets stimulated by THR and PMA
. For the protein kinase C experiments platelets were obtained from ra
ts fed a grain-based diet, and for the thrombin experiments they were
from rats fed purified diets. In the latter experiments, immature male
rats were fed for 2 weeks a low zinc diet (<1 mg/kg) ad libitum or a
zinc adequate (100 mg/kg) diet either ad libitum or pair-fed. Zinc def
iciency impaired the aggregation of platelets stimulated by 0.045 U/mL
of THR by approximately 40%, and the external calcium uptake (0.03 U/
mL of THR) was decreased by approximately 30%. Staurosporine, a protei
n kinase C inhibitor, decreased thrombin-induced aggregation in a conc
entration-dependent manner, but it had no effect on the external calci
um uptake. While PMA had a synergistic effect with thrombin in the sti
mulation of platelet aggregation, it actually decreased the cytosolic-
free calcium response to thrombin. it is concluded that zinc deficienc
y impairs thrombin-stimulated platelet aggregation and calcium uptake
and that protein kinase C activity is essential for rat platelet aggre
gation. Protein kinase C does not stimulate calcium uptake and must ac
t downstream of the calcium uptake defect. A model of rat platelet act
ivation is presented depicting impaired Ca2+ uptake as the primary def
ect in zinc deficiency.