Cher-Rin Chong1, Saifei Liu1, Giovanni Licari1, Tamila Heresztyn2, Yuliy Y Chirkov1, Doan T Ngo1, John D Horowitz3. 1. Cardiology and Clinical Pharmacology Department, Basil Hetzel Institute, the Queen Elizabeth Hospital, Woodville, South Australia, Australia; University of Adelaide, Adelaide, Australia. 2. Cardiology and Clinical Pharmacology Department, Basil Hetzel Institute, the Queen Elizabeth Hospital, Woodville, South Australia, Australia. 3. Cardiology and Clinical Pharmacology Department, Basil Hetzel Institute, the Queen Elizabeth Hospital, Woodville, South Australia, Australia; University of Adelaide, Adelaide, Australia. Electronic address: john.horowitz@adelaide.edu.au.
Abstract
BACKGROUND: Hyperglycemia in patients with acute coronary syndromes is associated with poor outcomes, and its rapid correction with insulin infusion has been shown to restore platelet responsiveness to nitric oxide and to suppress superoxide (O2(-)) generation. Thioredoxin-interacting protein has emerged recently as a pivotal modulator of hyperglycemia-induced inflammation, O2(-) production, and impairment of nitric oxide signaling, but it is not known whether its expression in platelets can be downregulated rapidly. METHODS: In 12 hyperglycemic patients with acute coronary syndrome, we evaluated the putative role of thioredoxin-interacting protein suppression in the platelet nitric oxide response after reversal of hyperglycemia with insulin infusion. RESULTS: Insulin infusion for 13.0 ± 0.8 (standard error of the mean) hours decreased blood glucose level from 16.6 ± 1.6 mmol/L to 8.7 ± 1.4 mmol/L (P = .002). This induced (1) sensitization of antiaggregatory response to nitric oxide (from 6.5% ± 7.7% to 39.7% ± 7.0%, P < .0001); (2) improved endothelial progenitor cell function (from a median of 45 to 180 colony-forming units, P < .05); and (3) decreases of whole blood reactive oxygen species content (P < .05). However, there was no significant suppression of platelet thioredoxin-interacting protein expression (mean decrease, 59 arbitrary units; 95% confidence interval, -193 to +74). CONCLUSIONS: Correction of hyperglycemia in patients with acute coronary syndrome rapidly reverses oxidative stress, restoring both platelet nitric oxide responsiveness and endothelial progenitor cell function, but this process is largely or entirely independent of thioredoxin-interacting protein.
BACKGROUND:Hyperglycemia in patients with acute coronary syndromes is associated with poor outcomes, and its rapid correction with insulin infusion has been shown to restore platelet responsiveness to nitric oxide and to suppress superoxide (O2(-)) generation. Thioredoxin-interacting protein has emerged recently as a pivotal modulator of hyperglycemia-induced inflammation, O2(-) production, and impairment of nitric oxide signaling, but it is not known whether its expression in platelets can be downregulated rapidly. METHODS: In 12 hyperglycemicpatients with acute coronary syndrome, we evaluated the putative role of thioredoxin-interacting protein suppression in the platelet nitric oxide response after reversal of hyperglycemia with insulin infusion. RESULTS:Insulin infusion for 13.0 ± 0.8 (standard error of the mean) hours decreased blood glucose level from 16.6 ± 1.6 mmol/L to 8.7 ± 1.4 mmol/L (P = .002). This induced (1) sensitization of antiaggregatory response to nitric oxide (from 6.5% ± 7.7% to 39.7% ± 7.0%, P < .0001); (2) improved endothelial progenitor cell function (from a median of 45 to 180 colony-forming units, P < .05); and (3) decreases of whole blood reactive oxygen species content (P < .05). However, there was no significant suppression of platelet thioredoxin-interacting protein expression (mean decrease, 59 arbitrary units; 95% confidence interval, -193 to +74). CONCLUSIONS: Correction of hyperglycemia in patients with acute coronary syndrome rapidly reverses oxidative stress, restoring both platelet nitric oxide responsiveness and endothelial progenitor cell function, but this process is largely or entirely independent of thioredoxin-interacting protein.