Journal of Molecular Medicine

, Volume 83, Issue 2, pp 148–158

Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin

  • Cezary Watala
  • Justyna Pluta
  • Jacek Golanski
  • Marcin Rozalski
  • Malgorzata Czyz
  • Zygmunt Trojanowski
  • Józef Drzewoski
Original Article

DOI: 10.1007/s00109-004-0600-x

Cite this article as:
Watala, C., Pluta, J., Golanski, J. et al. J Mol Med (2005) 83: 148. doi:10.1007/s00109-004-0600-x

Abstract

Reduced effectiveness of the most common antiplatelet drug, acetylsalicylic acid (ASA, aspirin), in diabetes mellitus has been associated with a lowered platelet sensitivity to ASA and related to glycemic control in diabetic patients. Our objectives were (a) to monitor the chemical background of how chronic hyperglycemia affects platelet response to ASA in diabetes and (b) to study a chemical competition between the amount of bound acetyl residues and the extent of protein glycation in blood platelets. Using whole-blood impedance aggregometry and platelet function analyzer (PFA-100) we observed a reduced platelet response to ASA in diabetic patients (14% vs. 79% for PFA-100 collagen-epinephrine occlusion time) and an association between the index of glycemic control and platelet refractoriness to ASA (rS=−0.378). Impaired platelet response to ASA was related to enhanced platelet protein glycation (3.6±0.4 in diabetes vs. 2.3±0.4 µmol fructosamine/µg protein in control) and reduced incorporation of acetyl residue into proteins of platelets from diabetic patients (47.4±2.0 in control vs. 33.1±0.7 µmol acetyl/µg protein in diabetic subjects). Incubation of blood platelets with increasing concentrations of glucose and ASA under in vitro conditions led to excessive modification in protein amino groups: glucose and ASA competed with each other in the course of nonenzymatic modifications, glycosylation, or acetylation, and their contributions to the occupancy of protein amino groups (R2=0.22 for glucose, R2=0.43 for ASA) were dependent upon the concentrations of glucose and ASA. Overall the effects of high glucose and high ASA on the overall occupancy of protein free amino groups are not additive. While at higher concentrations ASA overcomes the effects of hyperglycemia and retards glycation, high glucose makes acetylation less efficient, and therefore the resultant chemical modification becomes greatly reduced. In conclusion, diminished susceptibility of various platelet proteins and receptors on blood platelet membranes to acetylation and high ambient glucose might underlie the apparently differentiated sensitivity of blood platelets to ASA and determine platelet “insensitivity to aspirin” in diabetic patients

Keywords

Blood platelet reactivityDiabetes mellitusAcetylsalicylic acidAspirin resistanceAcetylation

Abbreviations

AA

Arachidonic acid

ASA

Acetylsalicylic acid

[14C]ASA

Acetyl-1-[14C]salicylic acid

BSA

Bovine serum albumin

CADP

Collagen and ADP

CEPI

Collagen and epinephrine

CS

Comprehensive score

CT

Closure time

WBEA

Whole-blood impedance (electrical) aggregometry

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Cezary Watala
    • 1
  • Justyna Pluta
    • 1
  • Jacek Golanski
    • 1
  • Marcin Rozalski
    • 1
  • Malgorzata Czyz
    • 2
  • Zygmunt Trojanowski
    • 3
  • Józef Drzewoski
    • 4
  1. 1.Department of Hemostasis and Hemostatic DisordersMedical University of LodzLodzPoland
  2. 2.Department of Medical ChemistryMedical University of LodzLodzPoland
  3. 3.Diabetological Unit, University Hospital no. 2Medical University of LodzLodzPoland
  4. 4.Department of Clinical PharmacologyMedical University of LodzLodzPoland