Alteration of platelet function contributes to microthrombus formation and may play an important role in the pathogenesis of diabetic micro- and macroangiopathies. However, the molecular mechanism for platelet dysfunction observed in patients with diabetes has not been fully elucidated. In this study, the direct effects of
hyperglycemia on platelet function in vitro were investigated.
Hyperglycemia increased
reactive oxygen species generation in human platelets, and this effect was additive with that of
collagen.
Thenoyltrifluoroacetone (TTFA), an inhibitor of mitochondrial electron transport chain complex II, and
carbonyl cyanide m-chlorophenylhydrazone (
CCCP), an uncoupler of oxidative phosphorylation, completely prevented the effects of
hyperglycemia, suggesting that
reactive oxygen species arise from the mitochondrial electron transport chain.
Hyperglycemia potentiated both platelet aggregation and the subsequent release of
platelet-derived growth factor AB induced by a nonaggregating subthreshold concentration of
collagen, which were also completely inhibited by TTFA or
CCCP. Furthermore,
hyperglycemia was found to inhibit
protein tyrosine phosphatase (PTP) activity and increase phosphorylation of the
tyrosine kinase Syk in platelets exposed to
collagen.
Hyperglycemia-induced PTP inhibition and Syk phosphorylation were found to be completely prevented by TTFA,
CCCP, or Mn(III)tetrakis (4-benzoic acid)
porphyrin, a stable cell-permeable
superoxide dismutase mimetic. These results suggest that
hyperglycemia-induced mitochondrial
superoxide generation may play an important role in platelet dysfunction observed in patients with diabetes.