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. 2012 Nov;61(11):2913-21.
doi: 10.2337/db12-0040. Epub 2012 Jul 26.

High glucose inhibits the aspirin-induced activation of the nitric oxide/cGMP/cGMP-dependent protein kinase pathway and does not affect the aspirin-induced inhibition of thromboxane synthesis in human platelets

Isabella Russo  1 , Michela Viretto, Cristina Barale, Luigi Mattiello, Gabriella Doronzo, Andrea Pagliarino, Franco Cavalot, Mariella Trovati, Giovanni Anfossi
Affiliations

High glucose inhibits the aspirin-induced activation of the nitric oxide/cGMP/cGMP-dependent protein kinase pathway and does not affect the aspirin-induced inhibition of thromboxane synthesis in human platelets

Isabella Russo et al. Diabetes. 2012 Nov.

Abstract

Since hyperglycemia is involved in the "aspirin resistance" occurring in diabetes, we aimed at evaluating whether high glucose interferes with the aspirin-induced inhibition of thromboxane synthesis and/or activation of the nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) pathway in platelets. For this purpose, in platelets from 60 healthy volunteers incubated for 60 min with 5-25 mmol/L d-glucose or iso-osmolar mannitol, we evaluated the influence of a 30-min incubation with lysine acetylsalicylate (L-ASA; 1-300 μmol/L) on 1) platelet function under shear stress; 2) aggregation induced by sodium arachidonate or ADP; 3) agonist-induced thromboxane production; and 4) NO production, cGMP synthesis, and PKG-induced vasodilator-stimulated phosphoprotein phosphorylation. Experiments were repeated in the presence of the antioxidant agent amifostine. We observed that platelet exposure to 25 mmol/L d-glucose, but not to iso-osmolar mannitol, 1) reduced the ability of L-ASA to inhibit platelet responses to agonists; 2) did not modify the L-ASA-induced inhibition of thromboxane synthesis; and 3) prevented the L-ASA-induced activation of the NO/cGMP/PKG pathway. Preincubation with amifostine reversed the high-glucose effects. Thus, high glucose acutely reduces the antiaggregating effect of aspirin, does not modify the aspirin-induced inhibition of thromboxane synthesis, and inhibits the aspirin-induced activation of the NO/cGMP/PKG pathway. These results identify a mechanism by which high glucose interferes with the aspirin action.

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Figures

FIG. 1.
FIG. 1.
Effect of platelet exposure to different L-ASA concentrations on closure time of PFA-100 CEPI in the presence of different glucose concentrations. Box plots range from the first to the third quartile; bold line in the boxes represents the median. Wiskers range from the minimum to the maximum of the measured values in the absence of outliers. Dots represent outliers with values between 1.5 and 3 (interquartile range); asterisks represent extreme outliers. Statistical analysis, carried out by Wilcoxon signed rank test, shows that glucose (5, 15, and 25 mmol/L; n = 34) did not modify closure time responses in the presence of the different L-ASA concentrations.
FIG. 2.
FIG. 2.
Effect of platelet exposure to different glucose concentrations on the L-ASA–induced inhibition of platelet aggregation responses to NaA and ADP. Statistical analysis, carried out by two-factor within subject ANOVA for repeated measures, shows that the response to L-ASA on platelet aggregation induced by NaA (A) and ADP (B) did not differ between 5 and 15 mmol/L glucose, whereas it differed between 5 and 25 mmol/L glucose (P < 0.0001 for both agonists) and between 15 and 25 mmol/L glucose (P < 0.0001 for both agonists; n = 24).
FIG. 3.
FIG. 3.
Effect of preincubation with amifostine on the L-ASA–induced inhibition of platelet aggregation in response to NaA and ADP in the presence of different glucose concentrations. At 5 mmol/L glucose (n = 9): amifostine vs. baseline and amifostine + L-ASA vs. L-ASA alone, P = NS for platelet aggregation induced by both NaA (A) and ADP (B). At 25 mmol/L glucose (n = 9): amifostine vs. baseline, P = NS for platelet aggregation induced by both NaA (A) and ADP (B); amifostine + L-ASA vs. L-ASA alone, P = 0.002 (Student paired t test) for platelet aggregation induced by NaA (A) and P < 0.0001 (Student paired t test) for platelet aggregation induced by ADP (B).
FIG. 4.
FIG. 4.
Effect of platelet exposure to different glucose concentrations on the L-ASA–induced inhibition of thromboxane synthesis in response to NaA and to ADP. Statistical analysis, carried out by two-factor within subject ANOVA for repeated measures, shows that TXB2 values did not differ between 5 and 25 mmol/L glucose either in the absence of L-ASA or in the presence of each L-ASA concentration for both NaA (n = 24) (A) and ADP (n = 24) (B).
FIG. 5.
FIG. 5.
Effect of L-ASA on platelet NOS activity in the presence of different glucose concentrations with and without preincubation with amifostine. At 5 mmol/L glucose (n = 12): L-ASA vs. baseline, P < 0.0001; amifostine vs. baseline and amifostine + L-ASA vs. L-ASA alone, P = NS (Student paired t test). At 25 mmol/L glucose (n = 12): L-ASA vs. baseline, P = NS; amifostine vs. baseline, P = NS; amifostine + L-ASA vs. L-ASA alone, P < 0.05; amifostine + L-ASA vs. amifostine alone, P < 0.04 (Student paired t test).
FIG. 6.
FIG. 6.
Effect of L-ASA on platelet cGMP in the presence of different glucose concentrations without and with the guanylate cyclase inhibitor MB and the NOS inhibitor l-NMMA. At 5 mmol/L glucose (n = 12): L-ASA vs. baseline, P < 0.003; MB + L-ASA vs. baseline, P = NS; l-NMMA + L-ASA vs. baseline, P = NS (Student paired t test). At 25 mmol/L glucose (n = 12): L-ASA vs. baseline, without or with MB or l-NMMA, P = NS (Student paired t test).
FIG. 7.
FIG. 7.
Effect of L-ASA on platelet VASP phosphorylation at serine 239 in the presence of different glucose concentrations. At 5 mmol/L glucose (n = 6): L-ASA vs. baseline, P < 0.001 (Student paired t test). At 25 mmol/L glucose (n = 6): L-ASA vs. baseline, P = NS (Student paired t test).
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