A high glucose level is associated with decreased aspirin-mediated acetylation of platelet cyclooxygenase (COX)-1 at serine 529: A pilot study

• Published in: Journal of proteomics 2019-02, Vol.192, p.258-266
• Main Authors: Finamore, Francesco, Reny, Jean-Luc, Malacarne, Sarah, Fontana, Pierre, Sanchez, Jean-Charles
• Format: Article
• Language: English
• ISSN: 1874-3919
• DOI: 10.1016/j.jprot.2018.09.007

Diabetes is a major risk factor for cardiovascular diseases. Although aspirin is considered a cornerstone of the prevention and treatment of atherothrombotic-related ischemic events, this antiplatelet drug appears to be less effective in patients with poorly controlled diabetes. It has been suggested that the glycation of platelet proteins plays a pivotal role in poor responsiveness to aspirin. However, a direct effect on the critical residue (serine 529, or Ser 529) of the catalytic pocket of cyclooxygenase 1 (COX-1) has never been demonstrated. This pilot study aimed to elucidate the impact of hyperglycaemia on aspirin acetylation of COX-1 using a targeted mass spectrometry approach. We observed that high glucose concentration had a direct impact on the level of acetylation of the COX-1 Ser 529 residue, whereas it's overall acetylation level remained unchanged. Moreover, the functional aspirin-induced inhibition of COX-1 was dose-dependently impaired as glucose concentrations increased. These in vitro findings were in line with data obtained using platelets from diabetic patients. These data provide new insights into the interplay between glucose and aspirin on platelet proteins and their effects on platelet COX-1. They also suggest a potential mechanistic explanation for the phenomenon of poor response to aspirin in diabetic patients. Data are available via ProteomeXchange with identifier PXD011204. Deciphering the mutual interplay between glucose and aspirin-mediated acetylation on platelet COX-1, might be of great interest as there is still a lack of information of the mechanism underlying this process that may contribute to the less-than expected response of platelets to aspirin, often observed in diabetes. [Display omitted] •The impact of high glucose concentrations and diabetes on aspirin effect was assessed on platelet COX-1.•Aspirin-mediated acetylation on Ser 529 significantly decreases in presence of high glucose levels and in hyperglycaemia.•The low acetylation level of Ser 529 is associated to an incomplete inhibition of COX-1 activity in presence of glucose.•The molecular docking of glucose around the catalytic pocket of COX-1 was calculated to explain the presented data.