Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction

Sho Ichi Yamagishi, Diane Edelstein, Xue-Liang Du, Michael Brownlee

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1491-1494
Number of pages4
JournalDiabetes
Volume50
Issue number6
StatePublished - 2001

Fingerprint

Platelet Activation
Superoxides
Hyperglycemia
Collagen
Thenoyltrifluoroacetone
Blood Platelets
Protein Tyrosine Phosphatases
Reactive Oxygen Species
Electron Transport Complex II
Phosphorylation
Diabetic Angiopathies
Oxidative Phosphorylation
Electron Transport
Platelet Aggregation
Protein-Tyrosine Kinases
Superoxide Dismutase
carbonyl 3-chlorophenylhydrazone
mesoxalonitrile

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. / Yamagishi, Sho Ichi; Edelstein, Diane; Du, Xue-Liang; Brownlee, Michael.

In: Diabetes, Vol. 50, No. 6, 2001, p. 1491-1494.

Research output: Contribution to journalArticle

Yamagishi, Sho Ichi ; Edelstein, Diane ; Du, Xue-Liang ; Brownlee, Michael. / Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. In: Diabetes. 2001 ; Vol. 50, No. 6. pp. 1491-1494.
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